Islam Zmerli
email: zmerli.islem@gmail.com

Jean-Philippe Michel

Ali Makky
email: ali.makky@universite-paris-saclay.fr

for bimodal photothermal/photodynamic therapy of cancer

Keywords:

come

Multifunctional polydopamine-based nanoparticles: synthesis, physico-chemical properties and applications for bimodal photothermal/photodynamic therapy of cancer

Islam Zmerli, Jean-Philippe Michel, Ali Makky

To cite this version:

Islam Zmerli, Jean-Philippe Michel, Ali Makky. Multifunctional polydopamine-based nanoparticles: synthesis, physico-chemical properties and applications for bimodal photothermal/photodynamic therapy of cancer. Multifunctional Materials, 2021, 4 (2), pp.022001. 10.1088/2399-7532/abf0fa. hal-04225742

Introduction

The development of bio-inspired and bio-mimicking materials has become a predominant strategy for the design of novel nanomaterials with interesting potential functions and promising biomedical applications such as for the treatment of cancer [START_REF] Evangelopoulos | Bioinspired approaches for cancer nanotheranostics[END_REF][START_REF] Li | Recent advances of biomimetic nano-systems in the diagnosis and treatment of tumor[END_REF] and bacterial infections [3]. To this end, melanin pigments have gained growing interest among the bioinspired materials for the design of multifunctional nanomaterials for many biomedical applications. In fact, melanin pigments are ubiquitous natural biopolymers of dark color that can be found in many types of living organisms ranging from bacteria [START_REF] Nosanchuk | The contribution of melanin to microbial pathogenesis[END_REF] and fungi [START_REF] Eisenman | Synthesis and assembly of fungal melanin[END_REF] to plants [START_REF] Glagoleva | Melanin Pigment in Plants: Current Knowledge and Future Perspectives[END_REF] and mammals [START_REF] Naaz | Biochemical aspects of mammalian melanocytes and the emerging role of melanocyte stem cells in dermatological therapies International journal of health sciences[END_REF]. The key enzyme of melanogenesis in many microorganisms and animals is the tyrosinase [START_REF] Nunes | Chapter 20 -Tyrosinases-physiology, pathophysiology, and applications[END_REF]. While these pigments contribute to the pathogenesis of some microorganisms and to the seeds color in plants, they play different physiological roles in mammals. In these latter species, melanin pigments can be found in various parts of living organisms such as skin, eye, hair and brain medulla, and can be divided into different groups depending on their origin and location, including eumelanin, pheomelanin, neuromelanin, allomelanin, etc. [START_REF] Xie | Natural Eumelanin and Its Derivatives as Multifunctional Materials for Bioinspired Applications[END_REF][START_REF] Miranda | Melanogenesis, tyrosinase expression, and reproductive differentiation in black and white truffles (Ascomycotina) Pigment cell research[END_REF]. Due to their intrinsic properties, natural melanin pigments and their vesicles have been extracted from natural sources such as cuttlefish ink [START_REF] Jiang | Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors[END_REF], hair [START_REF] Li | Lysozyme-Assisted Photothermal Eradication of Methicillin-Resistant Staphylococcus aureus Infection and Accelerated Tissue Repair with Natural Melanosome Nanostructures[END_REF] and skin [START_REF] Young | The Extraction of Melanin from Skin with Dilute Alkali[END_REF], however due to the complicated extraction and purification procedures, synthetic methods of melanin derivatives were required.

On another hand, the astonishing strong adhesion of marine mussels, Mytilus edulis, to diverse wet surfaces has been a great inspiration for the design of new biomaterials for surface coating [START_REF] Sedo | Catechol-based biomimetic functional materials Advanced materials[END_REF][START_REF] Yu | Synthetic Polypeptide Mimics of Marine Adhesives[END_REF][START_REF] Dalsin | Mussel adhesive protein mimetic polymers for the preparation of nonfouling surfaces[END_REF][START_REF] Statz | New peptidomimetic polymers for antifouling surfaces[END_REF]. This mussel unique robust adhesion was long investigated and was ascribed to the Mytilus edulis foot proteins (Mefps), particularly Mefp-5, which is found preferentially near the adhesive plaque/substrate interface and is able to glue surfaces with a high strength and stability [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF]. These Mefps were found to be rich in 3,4-dihydroxyphenylalanine (DOPA)

and lysine residues [START_REF] Waite | Reverse engineering of bioadhesion in marine mussels[END_REF][START_REF] Yu | Role of l-3,4-Dihydroxyphenylalanine in Mussel Adhesive Proteins[END_REF][START_REF] Waite | Polyphosphoprotein from the adhesive pads of Mytilus edulis[END_REF]. Inspired by these proteins' chemistry, Messersmith's group reported that, under mild alkaline conditions, dopamine hydrochloride can spontaneously undergo an oxidative self-polymerization process to afford a strong black-colored coating material, called "polydopamine" (PDA), able to adhere to the surface of all tested inorganic and organic substrates [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF] (Figure 1A). Indeed, dopamine is a DOPA derivative catecholamine bearing both catechol and amine functions and represents hence a powerful building block for the elaboration of Mefps mimics.

The dopamine auto-oxidation was investigated long before by [START_REF] Binns | Studies related to the chemistry of melanins. Part XIII. Studies on the structure of dopamine-melanin[END_REF] for the synthesis of a "dopamine-melanin" material in studies related to the chemistry of melanins [START_REF] Binns | Studies related to the chemistry of melanins. Part XIII. Studies on the structure of dopamine-melanin[END_REF]. However, since the pioneering report by Lee et al., polydopamine has mainly emerged as an attractive organic coating material, superior to the common surface modification strategies like layer-by-layer assembly or self-assembled monolayers [START_REF] Ryu | Polydopamine Surface Chemistry: A Decade of Discovery[END_REF][START_REF] Lee | Material-Independent Surface Chemistry beyond Polydopamine Coating[END_REF]. Interestingly, owing to the abundant nucleophilic and electrophilic reactive sites [25], polydopamine coatings were proven able to undergo secondary reactions, offering thus an interesting platform for the immobilization of a large repertoire of molecules on the polydopaminemodified substrates [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF]. Hence, polydopamine served as a versatile surface coating and functionalization material in diverse material science fields and allowed the development of diverse polydopamine-coated nanostructures including multifunctional core@shell nanocomposites and hollow nanocapsules or nanotubes [START_REF] Ryu | Polydopamine Surface Chemistry: A Decade of Discovery[END_REF][START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF][START_REF] Ye | Bioinspired catecholic chemistry for surface modification[END_REF][START_REF] Lynge | Polydopamine-a nature-inspired polymer coating for biomedical science[END_REF].

Besides, as it shares the same precursor molecules, synthesis mechanisms and similar structural and physicochemical properties with natural eumelanin pigment, polydopamine is also regarded as a synthetic analogue of naturally occurring melanin (Figure 1B). Actually, the oxidative process yielding polydopamine coatings leads simultaneously to the formation of aggregates in the bulk solution. Efforts have been devoted to the valorization of such aggregates and the control of polydopamine growth processes in order to obtain stable nanocolloids, that can be used as melanin-like nanoparticles. Eumelanin, a brown-black melanin derived from Tyrosine oxidation into L-DOPA displays a number of intriguing physico-chemical properties at the origin of their important roles in diverse biochemical processes and biological activities. For instance, owing to its broad absorption spectra covering the entire UV-visible-NIR regions, its radical scavenging effect, redox active metal ions chelation and anti-oxidant ability, its fast non-radiative relaxation process and so forth, eumelanin exhibits important photo-protective and anti-oxidation functions and contributes to the homeostasis of several biochemical systems [START_REF] Xie | Natural Eumelanin and Its Derivatives as Multifunctional Materials for Bioinspired Applications[END_REF]. Importantly, eumelanin is biologically degradable into non-toxic metabolites. These inherent properties are closely related to their chemical composition and molecular buildup. Similarly, owing to its outstanding physico-chemical properties, polydopamine eumelanin-like nanoparticles emerged as powerful biocompatible and biodegradable nanoplatforms with interesting properties such as anti-oxidant effects, photothermal conversion ability and photoacoustic

properties [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF][START_REF] Tran | Current Advances in the Utilization of Polydopamine Nanostructures in[END_REF][START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF][START_REF] Cheng | Versatile Polydopamine Platforms: Synthesis and Promising Applications for Surface Modification and Advanced Nanomedicine[END_REF].

Altogether, due to the advantageous concomitant features derived from both mussel-and melanin-mimicking properties, polydopamine has attracted extensive attention for the design of novel smart nanoplatforms with a plethora of possible applications including in energy and environmental materials sciences but particularly in the biomedical field where it emerged as a material of choice for the elaboration of a diverse multifunctional nanosystems of great potential in fields like cancer therapy (Figure 2), infections treatment, biosensing and bioimaging, tissue engineering, etc. and their applications in different domains [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF][START_REF] Tran | Current Advances in the Utilization of Polydopamine Nanostructures in[END_REF][START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF][START_REF] Cheng | Versatile Polydopamine Platforms: Synthesis and Promising Applications for Surface Modification and Advanced Nanomedicine[END_REF][START_REF] Mrówczyński | Polydopamine-Based Multifunctional[END_REF][START_REF] Huang | Recent Advances and Progress on Melanin-like Materials and Their Biomedical Applications[END_REF][START_REF] Park | Recent advances in melanin-like nanomaterials in biomedical applications: a mini review[END_REF][START_REF] Liu | Recent developments in polydopamine: an emerging soft matter for surface modification and biomedical applications[END_REF][START_REF] Batul | Recent progress in the biomedical applications of polydopamine nanostructures[END_REF]. However, recent comprehensive reviews about the physico-chemical prospects governing the formation, behavior and functions of polydopamine nanomaterials are still lacking. Therefore, in this review, we will outline the significant known features and bridge them with the recent advancement in the understanding of the structure-properties-processing relationships. Throughout this review, the discussion will only concern PDA-based particulate nanosystems, i.e., PDA nanospheres, PDA nanocapsules, and PDA-coated nanosystems. First, we will describe the preparation methods reported for the fabrication of polydopamine products and the major key factors allowing to elaborate polydopamine colloidal structures and shells of controlled properties.

Next, we will overview the most relevant structural models proposed, to date, for polydopamine and the underlying formation mechanisms. Thereafter, we will discuss the fundamental physico-chemical properties of polydopamine nanomaterials and elucidate their direct implementation in cancer treatment and/or diagnosis, in particular the drug delivery of anticancerous molecules and the photo-based cancer therapies mainly photothermal therapy (PTT) and photodynamic therapy (PDT). Analogies between polydopamine and eumelanin will be made in the different sections of this paper to give a general understanding of polydopamine properties.

Preparation strategies of polydopamine-based materials

The preparation methods of polydopamine nanomaterials have largely evolved from the first protocol described by Messersmith's group in 2007 [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF]. Generally, in presence of a substrate, with dimensions down to the nanoscale, a thin polydopamine layer can be deposited overtime on the substrate's surface, via the oxidation of dopamine precursor. Simultaneously, insoluble polydopamine aggregates are formed in the medium and continue to grow into particles. Many progresses have been achieved in the comprehension of the mechanisms governing polydopamine growth and its aggregation processes. In addition, several efforts have been devoted in the aim of expanding the synthetic toolbox of polydopamine materials and adjusting the set of experimental parameters for the formation of polydopamine shells or particles with strictly controlled morphological and physico-chemical properties. In this section, we will describe the most reported strategies applied to control polydopamine synthesis, particularly PDA nanocolloids and PDA-coated nanosystems. They are commonly categorized into three major approaches, namely the solution oxidation (Figure 3A), the enzymatic oxidation (Figure 3B) and the electropolymerization (Figure 3C) of dopamine monomers. We will discuss the different key parameters shown to have a great impact on the dopamine oxidation kinetics and consequently on the prepared polydopamine nanomaterials.

. Auto-oxidative polymerization in alkaline conditions

To date, the solution auto-oxidative self-polymerization of dopamine hydrochloride in mild alkaline solution (pH > 7.5) under ambient atmosphere remains the simplest and most common strategy used for the preparation of polydopamine products, due to its versatility, cost-effectiveness and reproducibility. Polydopamine synthesis occurs rapidly and is accompanied with a color change of the solution from colorless to pale brown turning progressively to dark brown or black.

At first, this method has been described for the preparation of PDA coatings and was achieved in an aqueous Tris buffer solution (pH 8.5) [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF]. Soon later, this protocol was further adapted to produce polydopamine coatings of controlled thicknesses and morphologies and more interestingly to valorize the polydopamine aggregates formed in the bulk solution. It was proposed that the oxidation of dopamine monomer leads to the formation of a dopaminequinone moiety, which undergoes cyclization and further oxidation and rearrangement processes, yielding eventually polydopamine products. Kinetics studies have generally agreed that the first oxidation step of the deprotonated dopamine was the rate-determining step in polydopamine formation. The following intramolecular cyclization process was relatively rapid. Consequently, several strategies have emerged based on controlling the oxidation reaction kinetics mainly through tailoring the following experimental conditions: the solution pH, the used buffer/solvent, dopamine concentration and the temperature (Figure 3A).

Choice of solvent and pH value

The pH value of the reaction solution is a vital factor allowing control the kinetics of dopamine auto-oxidative self-polymerization. Based on the generally adopted mechanism of polydopamine synthesis (Scheme 1A), a basic pH appears crucial for the consumption of the hydrogen protons produced as polydopamine formation progresses. This allows the shift of the redox equilibrium towards polydopamine production [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF] and an increase in the initial solution pH leads to the acceleration of dopamine oxidation rates [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF][START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF]. Hence, by increasing the initial pH, an increase in the thickness of the PDA deposited layer could be achieved in the case of polydopamine coatings [START_REF] Ball | Kinetics of polydopamine film deposition as a function of pH and dopamine concentration: Insights in the polydopamine deposition mechanism[END_REF], while when producing polydopamine nanoparticles, a decrease in the particles size could be obtained [START_REF] Ho | The pH-controlled nanoparticles size of polydopamine for anti-cancer drug delivery[END_REF]. The choice of the reactant solvent is another critical factor of a great impact on the outcomes of dopamine oxidative polymerization.

Alkaline buffers:

To date, the use of Tris buffer (at pH 8.5) as a basic polymerization initiator remains the most common method used for the preparation of polydopamine coatings [START_REF] Ponzio | Oxidant Control of Polydopamine Surface Chemistry in Acids: A Mechanism-Based Entry to Superhydrophilic-Superoleophobic[END_REF]. It is worth noting that the structural investigation of the as-prepared coatings revealed that Tris could be incorporated in polydopamine scaffold via covalent coupling between its primary amine and the dopamine-quinone intermediate, which risks impacting the materials properties [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][START_REF] Vecchia | Tris Buffer Modulates Polydopamine Growth, Aggregation, and Paramagnetic Properties[END_REF].

However, Tris incorporation in PDA matrix was found to be prevalent only at the highest Tris/dopamine molar ratios [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]. To avoid such interference, other amine-free alkaline buffers were reported for the preparation of PDA coatings, in particular phosphate and bicarbonate buffers [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][START_REF] Vecchia | Tris Buffer Modulates Polydopamine Growth, Aggregation, and Paramagnetic Properties[END_REF][START_REF] Bernsmann | Dopamine-melanin film deposition depends on the used oxidant and buffer solution[END_REF].

NaOH solution:

To fabricate colloidal PDA nanospheres, further acceleration of the dopamine oxidation kinetics is needed. The synthesis of nano-sized particles was reported for the first time in 2011 by Ju et al. [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF]. In their protocol, sodium hydroxide (NaOH) aqueous solution was used in replacement to the above-mentioned basic buffers, which affected considerably the kinetics of deprotonated dopamine's oxidation and allowed the production of nanoparticles with a size less than 100 nm. This protocol was later adopted by several groups for the synthesis of melanin-mimetic nanospheres [START_REF] Amin D R | Size Control and Fluorescence Labeling of Polydopamine Melanin-Mimetic Nanoparticles for Intracellular Imaging Biomimetics[END_REF][START_REF] Ho | The pH-controlled nanoparticles size of polydopamine for anti-cancer drug delivery[END_REF]. Later, Cho et al. investigated more in depth the hydroxide-ion mediated synthesis of stable polydopamine nanoparticles [START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF]. Considering their critical role in hydrogen abstraction during dopamine oxidation, it was found that the concentration of hydroxide ions influences directly the initial dopamine oxidation rate which determines the number of nuclei for nanospheres growth and enables the control of nanospheres diameter. Precisely, an increase of hydroxide ions concentration induced a linear acceleration of the oxidation rate and an early saturation of the solution with oxidized dopamine, leading therefore to the formation of more nucleation sites and consequently the production of smaller nanospheres [START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF]. Moreover, in the used hydroxide concentrations range, nanoparticles surface charge was highly negative (-44 mV) which prohibited particles aggregation and maintained their colloidal stability.

Although sodium hydroxide-mediated protocol was revealed efficient for the preparation of nano-sized PDA spheres with a reproducible fine control over their size and a good colloidal stability in water and biological media, large polydopamine aggregates were simultaneously produced in the reaction media, which necessitated an additional time-consuming purification step in order to be removed from the final preparation (by low-speed centrifugation, supplementary filtration, etc.) [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF][START_REF] Amin D R | Size Control and Fluorescence Labeling of Polydopamine Melanin-Mimetic Nanoparticles for Intracellular Imaging Biomimetics[END_REF]. Relatively high temperatures were also needed to reach the desired nanometric size (around 50 °C).

Water/organic solvents mixture or organic solvents:

Further efforts have been devoted to establish alternative preparation pathways offering a better control of the nanospheres size distribution. In this context, Lu's group reported for the first time a new protocol allowing the direct synthesis of monodisperse PDA nanospheres with a highly controlled size and morphology, using a water-ethanol mixed solvent (with 29 % (v/v) ethanol) in presence of ammonium hydroxide (NH 4 OH) as the basic catalyst [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF][START_REF] Ai | Sp2 C-Dominant N-Doped Carbon Sub-micrometer Spheres with a Tunable Size: A Versatile Platform for Highly Efficient Oxygen-Reduction Catalysts[END_REF].

The size of the as-prepared nanospheres could be tightly tuned in the range of several tens to hundreds of nanometers by varying the ammonia to dopamine molar ratio; higher ratios resulted in smaller nanoparticles. In a parallel study, Yan et al. highlighted the important role of water-alcohol mixed systems in the preparation of monodisperse spherical polydopamine nanoparticles; dopamine oxidation was conducted here in presence of Tris buffer at pH 8.5

and ethanol mixture [START_REF] Yan | Polydopamine spheres as active templates for convenient synthesis of various nanostructures[END_REF]. Interestingly, it was revealed that pure ethanol could impede dopamine polymerization [START_REF] Yan | Polydopamine spheres as active templates for convenient synthesis of various nanostructures[END_REF][START_REF] Jiang | Selecting water-alcohol mixed solvent for synthesis of polydopamine nano-spheres using solubility parameter[END_REF], which suggested that its introduction in the reactant medium as a co-solvent may offer a control over the polymerization rate and consequently over polydopamine particles growth process. To better explain all these findings, Jiang et al.

studied the formation of PDA particles achieved in ammonium hydroxide in presence of various alcohol-water mixtures and calculated the Hansen solubility parameter corresponding to each solvent system [START_REF] Jiang | Selecting water-alcohol mixed solvent for synthesis of polydopamine nano-spheres using solubility parameter[END_REF]. Their results demonstrated that the monodisperse PDA nanospheres could only be obtained at an appropriate volume fraction of ethanol ranging from 25% to 40%, which corresponded to the solvent mixture solubilizing at best the dopamine monomer. The highest conversion of dopamine was also obtained in this range of ethanol / water volume ratios. This alcohol-water system was not only limited to ethanol, but other alcohols such as methanol (at 10% or 20%) or 2-propanol (at 40%) were also proven to be efficient in the preparation of spherical monodisperse nanoparticles. Isopropyl alcohol and ethylene glycol were also reported in other studies for PDA nanoparticles preparation and showed similar results [START_REF] Yan | Polydopamine spheres as active templates for convenient synthesis of various nanostructures[END_REF].

It should be noted that dopamine polymerization could be also achieved in pure organic basic solvents like piperidine, which allowed to expand polydopamine applications to hydrolysable substrates coating but also to simultaneous immobilization of water-insoluble molecules [START_REF] You | Polydopamine coating in organic solvent for material-independent immobilization of water-insoluble molecules and avoidance of substrate hydrolysis[END_REF].

Dopamine concentration

Dopamine concentration is another key parameter which considerably affects polydopamine particles morphology and films deposition kinetics and characteristics [START_REF] Ball | Kinetics of polydopamine film deposition as a function of pH and dopamine concentration: Insights in the polydopamine deposition mechanism[END_REF][START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]. Increasing the initial dopamine concentration (from 0.1 to 5 g.l -1 ) resulted in a linear increase of the coating thickness [START_REF] Ball | Kinetics of polydopamine film deposition as a function of pH and dopamine concentration: Insights in the polydopamine deposition mechanism[END_REF][START_REF] Liu | Mussel-Inspired Polydopamine: A Biocompatible and Ultrastable Coating for Nanoparticles in Vivo[END_REF], but also in increasing the coatings surface roughness [START_REF] Vecchia | Tris Buffer Modulates Polydopamine Growth, Aggregation, and Paramagnetic Properties[END_REF]. The dopamine concentration first reported by Lee et al. and commonly used for general surface functionalization purposes is of 2 g.l -1 , however, lower concentrations (< 0.5 g.l -1 ) were preconized when polydopamine is used for the functionalization of nanostructures [START_REF] Liu | Mussel-Inspired Polydopamine: A Biocompatible and Ultrastable Coating for Nanoparticles in Vivo[END_REF]. In fact, the decrease of dopamine concentration to such low values allowed to effectively reduce the formation of polydopamine particles and thus their aggregation limiting the inevitable increase of PDA shells roughness [START_REF] Liu | Mussel-inspired polydopamine: A biocompatible and ultrastable coating for nanoparticles in vivo[END_REF]. Furthermore, it should be taken into account that dopamine concentration can also impact the molecular composition of the polydopamine products, in particular the relative proportions of cyclized and uncyclized units. In fact, at very low concentrations of this catecholamine (0.1 g.l -1 ), a larger ratio of cyclized indole units is obtained [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]. Dopamine concentration should also be properly adjusted for the preparation of monodisperse polydopamine nanoparticles, since unstable small nanospheres were obtained at low dopamine concentrations, while high values led to large nanospheres with an irregular shape [START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF]. Hence, tailoring dopamine concentration in the range yielding monodisperse nanoparticles allows the control of nanoparticles size and yield [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF][START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF][START_REF] Zmerli | Bioinspired polydopamine nanoparticles: synthesis, nanomechanical properties, and efficient PEGylation strategy[END_REF].

Temperature

The experimental temperature is another important factor that has to be carefully adjusted in order to control dopamine oxidation rates. Indeed, increasing the reaction temperature resulted in accelerated polydopamine deposition rates, leading to thicker and more hydrophilic polydopamine coatings in comparison to those formed at lower temperatures [55]. On the other hand, in the case of polydopamine nanoparticles production, increasing the temperature gave rise to smaller nanospheres with higher yields [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF][START_REF] Zmerli | Bioinspired polydopamine nanoparticles: synthesis, nanomechanical properties, and efficient PEGylation strategy[END_REF], which could be explained by enhanced dopamine oxidation kinetics. Cho et al. suggested that the temperature can impact the size of polydopamine nanospheres via different modalities [START_REF] Cho | Hydroxide ion-mediated synthesis of monodisperse dopamine-melanin nanospheres[END_REF]. At high values, the hydroxide ions concentration would increase as a result of pK water decrease, which leads to more nucleation sites and eventually smaller nanoparticles.

Templates

To date, the traditional template-free synthesis strategy based on the simple dopamine polymerization in alkaline aqueous or water-ethanol solutions remains largely adopted for the preparation of the PDA-based nanoplatforms. However, several templates-guided approaches have been also developed, permitting to further monitor dopamine polymerization and to shape polydopamine-based nanostructures into colloidal polydopamine nanoparticles, hollow nanocapsules or tubes, mesoporous nanoparticles, etc.

For instance, a reverse microemulsion-based method was employed to prepare relatively small monodisperse polydopamine nanospheres with a tunable size ranging from 25 to 43 nm [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF]. In this method, ammonium hydroxide was used as the aqueous phase and was added to a mixture of cyclohexane, used as the oil phase, and Igepal CO-520, used as the surfactant.

After sonication and stirring, ammonia aqueous nanosized droplets are formed in the oil cyclohexane phase and act as a confined nanoreactor for the synthesis of polydopamine nanospheres, with a tunable size obtained by tailoring the amount of ammonium hydroxide and the reaction temperature.

Besides, polydopamine nanoparticles synthesis could also be controlled through the addition of templating molecules such as surfactants [START_REF] Ponzio | Role of surfactants in the control of dopamine-eumelanin particle size and in the inhibition of film deposition at solid-liquid interfaces[END_REF], polyelectrolytes [START_REF] Mateescu | Polyelectrolytes to produce nanosized polydopamine[END_REF] and other polymers [START_REF] Zhang | Assembly of poly(dopamine) films mixed with a nonionic polymer[END_REF]. Cationic and anionic surfactants (like hexadecyltrimethylammonium bromide (HTAB) and sodium dodecylsulfate (SDS), respectively) [START_REF] Ponzio | Role of surfactants in the control of dopamine-eumelanin particle size and in the inhibition of film deposition at solid-liquid interfaces[END_REF] allowed the preparation of small nanoparticles with a tunable size that could be considerably decreased by increasing of surfactant's concentration. For the highest concentrations of surfactants, exceeding their critical micellar concentrations, nanoparticles could reach a range of sizes only slightly higher than those of surfactants micelles [25]. It was proposed that surfactants interact with dopamine and act as templates for confined polydopamine growth. The structure of the as-prepared polydopamine was similar to the conventionally produced polydopamine. Similar to surfactants, a vast repertoire of polyelectrolytes were found effective in controlling the size of PDA nanospheres in a concentration-dependent manner [START_REF] Mateescu | Polyelectrolytes to produce nanosized polydopamine[END_REF]. It was proposed that the mechanisms by which polyelectrolytes act may differ depending on their chemical nature. As an example, it was suggested that polycations bearing primary amin functions, like poly(allylamine hydrochloride), would interact covalently with the quinone groups of oxidized dopamine units and small polydopamine aggregates and act as "capping agents" limiting preferentially polydopamine formation near the polyelectrolyte and yielding, for sufficiently high polyelectrolyte concentrations, nanoparticles slightly larger than the polyelectrolyte diameter.

Several other templating molecules were reported in the literature for the controlled preparation of polydopamine-based nanomaterials, including certain proteins like human serum albumin [START_REF] Chassepot | Human serum albumin and other proteins as templating agents for the synthesis of nanosized dopamine-eumelanin Journal of colloid and interface science[END_REF] which allowed the increase of dopamine oxidation rates and yielded small stable biocompatible polydopamine nanoparticles. Interestingly, by screening the proteins of skin melanocytes found usually surrounding eumelanin, a specific amino acids diad in proteins, L-lysine (K) -L-glutamic acid (E), was found particularly efficient in the oxidation control process [START_REF] Bergtold | Mimicking the Chemistry of Natural Eumelanin Synthesis: The KE Sequence in Polypeptides and in Proteins Allows for a Specific Control of Nanosized Functional Polydopamine Formation[END_REF][START_REF] El Yakhlifi | Polydopamine as a stable and functional nanomaterial Colloids and Surfaces B[END_REF]. This KE diad would likely play a templating effect in polydopamine nanoparticles assembly via establishing synergistic interactions with dopamine (hydrogen bonding and -cation interactions) leading to an increased residence time of dopamine on this dipeptide as investigated by molecular dynamics simulations [START_REF] El Yakhlifi | Polydopamine as a stable and functional nanomaterial Colloids and Surfaces B[END_REF].

Template-guided dopamine polymerization pathways could also induce significant morphological changes of polydopamine assemblies. The most cited studies to this regard described the drastic impact of folic acid (FA) on the obtained PDA nanostructure [START_REF] Fan | Folic acid-polydopamine nanofibers show enhanced ordered-stacking via π-π interactions[END_REF][START_REF] Chyasnavichyus | Probing of Polymer Surfaces in the Viscoelastic Regime[END_REF]. In fact, when this molecule was added to dopamine solution, new aggregated nanobelts-and nanofibers-type structures were generated in the alkaline solution, preferentially at 60 °C. The authors proposed that the presence of FA favored the formation of porphyrin-like indolic tetramers and enhanced their ordered stacking through - stacking interactions, which would lead preferentially to an aggregation into the graphite-like ordered nanostructures.

Mesoporous polydopamine nanostructures could also be designed using triblock copolymer Pluronic F127 / 1,3,5-trimethylbenzene (TMB) emulsion composites as organic templates in

Tris buffer solution [START_REF] Chen | Nanoscale Polydopamine (PDA) Meets π-π Interactions: An Interface-Directed Coassembly Approach for Mesoporous Nanoparticles[END_REF][START_REF] Xing | Mesoporous polydopamine nanoparticles with codelivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy[END_REF]. It was proposed that the formation of the mesoporous structure was favored by the - stacking interactions between polydopamine aggregates and the electron-rich TMB. Primary polydopamine particles formed in the solution would diffuse into the organic TMB phase and subsequent packing of PDA particles would occur leading to the mesoporous nanostructure with particles and pores sizes tunable via varying TMB / F127 weight ratios. The preparation of polydopamine-based Janus composites as multifunctional nanoplatforms was also described in several reports, using diverse innovative strategies [START_REF] Zhang | Precise synthesis of unique polydopamine/mesoporous calcium phosphate hollow Janus nanoparticles for imaging-guided chemo-photothermal synergistic therapy[END_REF][START_REF] Shang | Bioinspired polydopamine coating as a versatile platform for synthesizing asymmetric Janus particles at an air-water interface[END_REF][START_REF] Xu | Electrostatic repulsion-controlled formation of polydopamine-gold Janus particles[END_REF][START_REF] Sheng | Dopamine Polymerization in Liquid Marbles: A General Route to Janus Particle Synthesis[END_REF]. In addition, hollow polydopamine (nano)capsules or (nano)tubes could also be obtained through polymerization of dopamine on soft templates (liquid-liquid interface) like emulsion droplets [START_REF] Qu | Interfacial Polymerization of Dopamine in a Pickering Emulsion: Synthesis of Cross-Linkable Colloidosomes and Enzyme Immobilization at Oil/Water Interfaces[END_REF][START_REF] Cui | Monodisperse polymer capsules: Tailoring size, shell thickness, and hydrophobic cargo loading via emulsion templating[END_REF][START_REF] Xu | Interfacial Basicity-Guided Formation of Polydopamine Hollow Capsules in Pristine O/W Emulsions-Toward Understanding of Emulsion Template Role[END_REF][START_REF] Zhuang | Polydopamine Nanocapsule: A Theranostic Agent for Photoacoustic Imaging and Chemo-Photothermal Synergistic Therapy[END_REF] and tetrahydrofuran-Tris buffer mixture [START_REF] Ni | Preparation of polydopamine nanocapsules in a miscible tetrahydrofuran-buffer mixture[END_REF] or on solid particulate templates of various sizes and shapes (solid-liquid interface) like SiO 2 , CaCO 3 , etc., followed by selective removal of the template core [START_REF] Postma | Self-Polymerization of Dopamine as a Versatile and Robust Technique to Prepare Polymer Capsules[END_REF][START_REF] Xue | Scalable Fabrication of Polydopamine Nanotubes Based on Curcumin Crystals[END_REF][START_REF] Dong | Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity[END_REF][START_REF] Tran | Synthesis of Polydopamine Hollow Capsules via a Polydopamine Mediated Silica Water Dissolution Process and Its Application for Enzyme Encapsulation Frontiers in[END_REF][START_REF] Yan | Polydopamine nanotubes: bio-inspired synthesis, formaldehyde sensing properties and thermodynamic investigation[END_REF].

Chemically-assisted oxidative polymerization of dopamine (using exogenous oxidants)

Despite its versatility and simplicity, the auto-oxidative pH-induced method is a relatively slow process demanding at least several hours to overnight incubation times [START_REF] Lee | Microwave-Accelerated Rapid, Chemical Oxidant-Free, Material-Independent Surface Chemistry of Poly(dopamine) Small[END_REF], and requires alkaline conditions in order to reach reasonable reactions rates [START_REF] Salomäki | Effects of pH and Oxidants on the First Steps of Polydopamine Formation: A Thermodynamic Approach[END_REF]. Besides, dissolved atmospheric oxygen is a critical element contributing to dopamine auto-oxidation and polymerization reactions, via hydrogen abstraction [START_REF] Ball | Comparison of synthetic dopamine-eumelanin formed in the presence of oxygen and Cu2+ cations as oxidants[END_REF][START_REF] Lee | Mussel-inspired surface chemistry for multifunctional coatings[END_REF][START_REF] Hong | Air/Water Interfacial Formation of Freestanding, Stimuli-Responsive, Self-Healing Catecholamine Janus-Faced[END_REF]. Indeed, when oxygen was eliminated from the solution, either by permanent nitrogen gas bubbling or by deoxygenation under vacuum, the incubation of dopamine in alkaline conditions, even at high pH values, did not visibly lead to polydopamine production [START_REF] Ju | Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property[END_REF].

Therefore, efforts have been made to overcome these limitations and alternative preparation strategies, based on the use of exogenous oxidants, have been developed to accomplish faster oxidation kinetics and further adjust polydopamine products properties. Such alternatives allowed, potentially, the production of polydopamine under neutral or acidic pH, which would be particularly interesting to expand polydopamine surface coating and one-pot drug/adjuvant co-loading applications to base-sensitive or insoluble substrates and molecules [25].

In fact, under high concentrations of oxygen (up to pure oxygen), the reaction kinetics increased drastically and allowed the deposition of highly homogenous and ultra-smooth PDA layers, achieved in much shorter deposition times [START_REF] Kim | Oxygen Concentration Control of Dopamine-Induced High Uniformity Surface Coating[END_REF]. Beside pure oxygen, other watersoluble oxidizing reagents were proven efficient to induce accelerated dopamine polymerization and could trigger polydopamine formation in mild alkaline conditions, but also in neutral or even acidic solutions [START_REF] Lee | Material-Independent Surface Chemistry beyond Polydopamine Coating[END_REF][START_REF] Ponzio | Oxidant Control of Polydopamine Surface Chemistry in Acids: A Mechanism-Based Entry to Superhydrophilic-Superoleophobic[END_REF][START_REF] Wei | Oxidant-induced Dopamine Polymerization for Multifunctional Coatings[END_REF][START_REF] Ball | Comparison of Synthetic Dopamine-Eumelanin Formed in the Presence of Oxygen and Cu2+ Cations as Oxidants[END_REF]. In this context, various oxidants have been employed including sodium periodate (NaIO 4 ), ammonium peroxydisulfate ((NH 4 ) 2 S 2 O 8 ) and potassium permanganate (KMnO 4 ), in addition to multiple other inorganic chemicals and metal ion additives such as Cu(II), Fe(III) and Mn(III) salts, etc. [START_REF] Bernsmann | Dopamine-melanin film deposition depends on the used oxidant and buffer solution[END_REF][START_REF] Salomäki | Effects of pH and Oxidants on the First Steps of Polydopamine Formation: A Thermodynamic Approach[END_REF][START_REF] Wei | Oxidant-induced Dopamine Polymerization for Multifunctional Coatings[END_REF][START_REF] Ball | Comparison of Synthetic Dopamine-Eumelanin Formed in the Presence of Oxygen and Cu2+ Cations as Oxidants[END_REF][START_REF] Salomäki | Polydopamine Nanoparticles Prepared Using Redox-Active Transition Metals[END_REF][START_REF] Zhao | Biopolymer-Assisted Manufacturing of Aluminum-Copper Nanoparticle Composites with Enhanced Sinterability[END_REF]. The choice of the used oxidant as well as its concentration has a major impact on the polymerization rates and the pathways favored during polydopamine assembling process [START_REF] Lee | Synthesis and gelation of DOPA-modified poly(ethylene glycol) hydrogels[END_REF].

Besides, mixtures of CuSO 4 /H 2 O 2 [START_REF] Zhang | CuSO4/H2O2-Induced Rapid Deposition of Polydopamine Coatings with High Uniformity and Enhanced Stability[END_REF], FeCl 3 /H 2 O 2 [START_REF] Zhu | A rapid deposition of polydopamine coatings induced by iron (III) chloride/hydrogen peroxide for loose nanofiltration[END_REF] or FeSO 4 /H 2 O 2 [START_REF] Jiao | Fast Preparation of Polydopamine Nanoparticles Catalyzed by Fe(2+)/H2O2 for Visible Sensitive Smartphone-Enabled Cytosensing[END_REF] were also used as oxidants for ultra-fast polydopamine shells or nanoparticles formation. Despite the great enhancement of polydopamine production kinetics, the possible effect of metal ions on the structure and properties of polydopamine should be taken into account. Indeed, polydopamine components (particularly catechol groups) exhibit a high affinity and complexation ability towards various metallic cations, leading to the inevitable incorporation of these latter in polydopamine matrix. Depending on the redox and complexation ability of the metal ion, this would lead to changes in polydopamine chemical composition (loss of nitrogen content, presence of metal content) and consequently to changes in its physico-chemical properties [START_REF] Lee | Material-Independent Surface Chemistry beyond Polydopamine Coating[END_REF][START_REF] Salomäki | Polydopamine Nanoparticles Prepared Using Redox-Active Transition Metals[END_REF][START_REF] Ball | Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings Biointerphases[END_REF].

Radical-, ionization-and microwave-assisted dopamine polymerization

In order to avoid chemical contamination of polydopamine nanomaterials encountered when using exogenous oxidants, alternative strategies have been developed to obtain fast dopamine polymerization kinetics, for the formation of polydopamine under neutral or even acidic conditions. Recently, Wang et al. reported a free radical-mediated strategy allowing further control the size of PDA nanoparticles prepared in a water/ethanol/ammonia mixture, via tuning the free radicals in the reaction medium [START_REF] Wang | Size control synthesis of melanin-like polydopamine nanoparticles by tuning radicals[END_REF]. Based on the speculation that polydopamine formation process could involve radical coupling pathways related to the generation of semi-quinone radical intermediates via dismutation reaction [START_REF] Wang | Surface Silverized Meta-Aramid Fibers Prepared by Bio-inspired Poly(dopamine) Functionalization[END_REF][START_REF] Wang | Bio-inspired polydopamine-coated clay and its thermo-oxidative stabilization mechanism for styrene butadiene rubber[END_REF], two strategies were tested and found effective to control polydopamine formation. The first one consisted in quenching the radical intermediates generated during PDA formation via the addition of strong radical scavengers (such as edaravone), which leads to the inhibition of nanoparticles growth. Whereas the second strategy was based on the addition of stable free radicals (such as PTIO•) which facilitates the seed formation process. Both strategies offer an interesting modality to control PDA nanoparticles diameter, while maintaining the characteristic chemical structure and physico-chemical properties of the conventional nanoparticles.

Free radical species triggering polydopamine formation can also be generated by providing external energy to the system via UV irradiation [START_REF] Du | Bio-inspired strategy for controlled dopamine polymerization in basic solutions[END_REF][100]. This light-induced method allowed the acceleration of dopamine polymerization under alkaline conditions and was also proven effective for polydopamine formation at neutral or acidic conditions (down to pH 2.0) [100].

Polydopamine formation could also be achieved by using visible light, under neutral conditions (pH = 7.0), in presence of 9-mesityl-10-methylacridinium ions as a photocatalyst [101]. Excited, this molecule can activate the solution dissolved oxygen, which triggers dopamine polymerization. The microwave-assisted polymerization is another method found to accelerate polydopamine formation in a chemical-free manner. Using this technique, only 15 minutes were needed to deposit a 18 nm film of PDA under 1000 W versus several hours for the traditional protocol [START_REF] Lee | Microwave-Accelerated Rapid, Chemical Oxidant-Free, Material-Independent Surface Chemistry of Poly(dopamine) Small[END_REF]. This enhancement effect of the polymerization kinetics was attributed to an increased radical generation by microwave irradiation and the resulting superheating effect. However, to the best of our knowledge, no previous studies have been reported about using this polymerization process for the preparation of PDA nanoparticles.

A hydrothermal process was also used to trigger dopamine oxidation and self-polymerization and allowed to extend polydopamine production to strong acidic environments (pH 1.0 and at 160 °C) [102]. The efficiency of this strategy was attributed to the pronounced auto-ionization of water under the high temperature and pressure employed, leading to the formation of hydroxyl ions in the bulk solution which are involved in dopamine oxidation reactions.

Enzymatic dopamine polymerization

The process of melanin biosynthesis in living organisms has inspired the development of a new approach for the preparation of polydopamine nanomaterials based on enzyme-catalyzed dopamine oxidation and self-polymerization. Several enzymes reported for the oxidation of phenolic and aromatic amines compounds have been employed as catalysts to trigger dopamine oxidative processes. For instance, laccase has been employed for the preparation of polydopamine nanoparticles and coatings (at pH ~ 5.5). In comparison to the conventional polydopamine products, the yielded products were interestingly more stable and uniform [103][104][105]. Horseradish peroxidase (HRP) was also efficient for rapid oxidation of dopamine in presence of hydrogen peroxide [106]. Also, using an urease catalytic reaction and based on the basification of the reaction medium coupled to urea hydrolysis, Li et al. developed an efficient approach offering control over dopamine polymerization and yielding polydopamine nanoparticles of tunable sizes that increase linearly with the increase of urea concentration

[107].
Although it is relatively more complicated than the conventional dopamine auto-oxidative protocol, the enzyme-catalyzed strategy represents an environmentally friendly method that is highly efficient for the preparation of polydopamine nanomaterials. Interestingly, being inspired by melanin biosynthesis, polydopamine produced using this method resembles at best to the naturally occurring melanin [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF][START_REF] Batul | Recent progress in the biomedical applications of polydopamine nanostructures[END_REF]. Furthermore, this approach is particularly advantageous for simultaneous immobilization of enzymes with preserved enzymatic activity in a one-pot preparation method.

Dopamine electro-polymerization strategy

Electropolymerization of dopamine emerged as an alternative approach mainly used for the preparation of polydopamine coatings [108][109][110][111]. Rapid polymerization and high deposition rates were obtained on diverse conductive nanostructures (TiO species that could trigger the nucleation of polydopamine nanoparticles at the plasma-liquid interface. As the process progressed, the solution pH shifted to acidic values (pH ~ 5) which inhibited the further growth of nanoparticles and allowed the control of their size [115].

Despite its simplicity, efficiency and possibility to be performed in a deoxygenated medium, the main drawback of this method is that polydopamine production can only occur on electrically conductive substrates, thus limiting its extent of applications.

To summarize, a wide variety of approaches have been stablished, to date, for a wellcontrolled preparation of polydopamine-derived nanomaterials. However, the exact structure and formation mechanisms of polydopamine are still not fully clear, as will be discussed in the following section.

Table1. The major methods used for the preparation of controlled polydopamine particulate nanostructures Tris buffer is the most used basic buffer, Choice of buffer impacts the polymerization kinetics and thickness, roughness, and paramagnetic properties of PDA layer. [START_REF] Vecchia | Tris Buffer Modulates Polydopamine Growth, Aggregation, and Paramagnetic Properties[END_REF] Sodium hydroxide / Water Preparation of PDA nanospheres, Few tens to few hundreds of nm Hydroxide ions concentration impacts the size of PDA nanoparticles. [37, 45-46] Ammonium hydroxide / Water / Ethanol Preparation of monodisperse PDA nanospheres, Few tens to few hundreds of nm Ammonia concentration impacts the size of PDA nanoparticles, Ethanol used at a volume fraction of 25% to 40% to obtain monodisperse nanoparticles. [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF][START_REF] Jiang | Selecting water-alcohol mixed solvent for synthesis of polydopamine nano-spheres using solubility parameter[END_REF] Reverse microemulsion:

-Ammonium hydroxide as aqueous phase -Cyclohexane as oil phase -Igepal as surfactant Preparation of small PDA nanospheres, Few tens of nm The size of dispersed ammonia droplets impacts the size of PDA nanoparticles. [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF] Basic conditions, In presence of templating molecules (polymers, polyelectrolytes, surfactants, proteins, etc.) Preparation of small PDA nanospheres, Nm to few tens of nm Templates act as confined environments for PDA synthesis, Templates concentration impacts the size of PDA nanoparticles. [START_REF] Ponzio | Role of surfactants in the control of dopamine-eumelanin particle size and in the inhibition of film deposition at solid-liquid interfaces[END_REF][START_REF] Mateescu | Polyelectrolytes to produce nanosized polydopamine[END_REF]116] Basic conditions, in presence of folic acid (FA) Preparation of PDA nanospheres/nanotubes, Few tens to few hundreds of nm FA and dopamine concentrations impact the morphology of PDA nanostructures. [START_REF] Fan | Folic acid-polydopamine nanofibers show enhanced ordered-stacking via π-π interactions[END_REF]117] Basic conditions (mainly buffers), in presence of core templates (soft templates or solid templates selectively removed) Preparation of PDA nanocapsules, Few tens to few hundreds of nm The size and shape of the cores define the size and shape of the hollow PDA structures [START_REF] Cui | Monodisperse polymer capsules: Tailoring size, shell thickness, and hydrophobic cargo loading via emulsion templating[END_REF][START_REF] Ni | Preparation of polydopamine nanocapsules in a miscible tetrahydrofuran-buffer mixture[END_REF][START_REF] Xue | Scalable Fabrication of Polydopamine Nanotubes Based on Curcumin Crystals[END_REF][START_REF] Dong | Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity[END_REF]118] Acidic, neutral or basic conditions, in presence of oxidants (like NaIO 4 ) Metal ions (like Cu (II))

Preparation of polydopamine nanoparticles and PDA-coated structures, Few nm to few hundreds of nm Choice of oxidant type and concentration impacts the kinetics of PDA polymerization, Oxidants and metal ions impact the structure of PDA and the thickness and roughness of the coating, Fast polymerization kinetics are obtained in comparison to conventional methods. [START_REF] Salomäki | Effects of pH and Oxidants on the First Steps of Polydopamine Formation: A Thermodynamic Approach[END_REF][START_REF] Wei | Oxidant-induced Dopamine Polymerization for Multifunctional Coatings[END_REF][START_REF] Salomäki | Polydopamine Nanoparticles Prepared Using Redox-Active Transition Metals[END_REF] Basic conditions (mainly ammonia), in presence of free radicals or radical scavengers Preparation of PDA nanospheres, Few tens to few hundreds of nm These additives allow radical tuning in the solution and a control of PDA polymerization and of the size of PDA nanoparticles. [START_REF] Wang | Size control synthesis of melanin-like polydopamine nanoparticles by tuning radicals[END_REF] Enzymatic polymerization (like laccasemediated polymerization) Preparation of PDA nanoparticles or PDAcoated nanostructures, Few tens to few hundreds of nm Preparation of stable and uniform nanostructures, resembling to melanin materials, Possible simultaneous immobilization of active enzymes on the yielded structures, Green products. [103,[105][106] Electro-polymerization / Plasmamediated electrochemistry Preparation of PDA-coated nanostructures or PDA nanospheres, Few nm to few hundreds of nm Exclusively used to coat conductive nanostructures like TiO 2 or Fe 3 O 4 , Fast polymerization kinetics are obtained in comparison to conventional methods, Ultra-small fluorescent PDA nanospheres were obtained. [112][113]115]

Polydopamine structural models and formation mechanisms

Since polydopamine discovery, numerous studies devoted to the investigation of polydopamine molecular structure and its buildup mechanism have been reported [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][119][120][121][122][123][124]. However, despite the great efforts invested, the detailed chemical composition of polydopamine is not fully understood yet and the elucidation of a definite structural model is still a long-lasting debate that has not yet come to its end. In fact, polydopamine's insoluble nature in common aqueous and organic solvents [119][120]124] made it difficult to investigate its structure by means of conventional analytical techniques usually applied for polymers molecular weights characterization [124][125]. Besides, it is accepted that polydopamine composition has a marked chemical heterogeneity and can depend on the preparation method and experimental conditions, as explained above [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][START_REF] Bernsmann | Dopamine-melanin film deposition depends on the used oxidant and buffer solution[END_REF], which makes the elucidation of an exact structure more challenging.

Various techniques were applied to uncover polydopamine composition, including mainly mass spectroscopic analyses, solid-state nuclear magnetic resonance (ss NMR), X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy along with other analytical methods. Theoretical approaches based on molecular energies calculations were also employed in order to provide more insights into polydopamine molecular organization [120,123,126]. Moreover, as previously stated, polydopamine is commonly considered as a eumelanin-like material and there is a general agreement that polydopamine shares formation steps with eumelanin biosynthesis.

Therefore, comparative structural studies were also undertaken to help bring more understanding of polydopamine characteristic molecular features [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][126][127].

Altogether, structural investigations carried out on PDA products (particles and/or coatings) led to controversial models that fall into three main hypotheses. The first one holds that polydopamine has a polymeric nature wherein dopamine and/or its oxidation derivatives are covalently linked via aryl-aryl coupling. The second theory suggests a supramolecular assembly arising from 3-dimensional association of monomeric units held together via weak interactions such as π-π stacking, Hydrogen bonding (H-bonding), charge transfer or π -cation interactions. The third structural model on the other hand is based on the contribution of both covalent and non-covalent interactions occurring at different stages of the polymerization process and leading to the black insoluble polydopamine products.

Scheme 1. (A)

The generally agreed dopamine auto-oxidation process, leading to the formation of polydopamine building units, (B) Structural models proposed for polydopamine generated from covalent polymerization pathways or physical self-assembling processes.

Covalent polymerization

While introducing polydopamine, Messersmith's group proposed a chemical structure and a formation mechanism on the basis of a time-of-flight secondary ion mass spectrometry (TOF-SIMS) and XPS data [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF]. A major mass peak was detected at m/z 445 and was attributed to a trimer of [START_REF] Eisenman | Synthesis and assembly of fungal melanin[END_REF]. This trimer was suggested to originate from the fragmentation of a long-chain polymer of similar composition, which led the authors to suggest that polydopamine is a polymeric material arising from a covalent association of DHI units via biphenyl-type covalent bonds (Scheme 1B, structure I). Based on this observation, a polymerization mechanism similar to that of eumelanin biosynthesis was proposed, wherein the initial driving force consists in the oxidation of dopamine monomer under oxidative alkaline conditions leading to dopamine-quinone formation. This component undergoes then an intra-molecular cyclization (by 1,4 Michael-type addition of the amino group to the phenyl-quinone system) which generates a leukodopaminechrome moiety whose further oxidation and rearrangement leads to the formation of the 5,6-dihydroxyindole. The further oxidation of DHI units generates 5,6-indolequinone and induces spontaneous inter-molecular cross-linkages by dehydrogenerative C-C bond formation at positions 2, 4 and 7 of the indole moieties, allowing to yield the black insoluble eumelanin-like polydopamine polymer [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF].

However, this polymerization process known as eumelanin-like poly(indole) structural model became later on an active area of investigation. In fact, chemical differences were noticed when polydopamine products were compared to pure DHI-polymer (generated from DHI units as exclusive starting monomers) [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]128]. Furthermore, mass spectroscopic analyses performed by other groups [128][129][130][131] on similarly prepared PDA materials did not reveal the presence of the peak at m/z 445 reported by Messersmith's group, and the wide set of analytical methods employed revealed the existence of diverse functional groups referring to the contribution of various moieties as key structural units in polydopamine buildup. For instance, clear experimental evidence about the presence of primary amines, quinone moieties or carboxylic groups has been widely reported throughout the literature [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]120,123]. These observations indicated that PDA would not be solely made of polymerized DHI units as proposed. Indeed, since the overall process of dopamine conversion to DHI was demonstrated to be relatively slow [128,132], dopamine monomer and the various intermediates derived from its oxidation process are very likely to be concommitly present in the reaction solution.

This would suggest that multiple synthesis pathways involving various kinetics key control points and different intermediates and types of connections (covalent or physical) may occur and lead to a more heterogeneous composition for polydopamine materials.

Non-covalent self-assembling

In this context, a different perspective of polydopamine formation was advanced by Dreyer et al. [119] who highlighted the important contribution of non-covalent interactions in this process. They postulated that polydopamine consists in a supramolecular aggregate of monomers lacking any covalent bond. The monomeric building units, consisting here in 5,6dihydroxyindoline and its dione derivative primarily, are entirely held together through a combination of H-bonding, π- stacking and charge transfer complexation. In fact, a detailed study conducted on PDA aggregates, using a variety of solid-state spectroscopic and crystallographic techniques, indicated the presence of these cyclized nitrogenous indolinetype species where the carbon atoms in position 4 and 7 of the aryl core were rather tertiary (hydrogenated). This observation ruled out the covalent model suggested by Lee et al.[18].

Alternatively, Dreyer et al. proposed a quinhydrone-like assembly that is further connected via π-π stacking favored by the d-spacing of 3.8 Å consistent with that observed in other πstacked materials [119,133]. Such spacing was found to likely facilitate or result from charge transfer between the faces of polydopamine building units (Scheme 1B, structure II).

Another entirely physical structure was identified by Hong et al. wherein dopamine units interfere with DHI moieties to build a supramolecular self-assembled block as a significant component trapped in polydopamine network [120]. In fact, the authors could identify a robust physically self-assembled [(Dopamine) 2 /DHI] trimeric complex entirely arising from non-covalent interactions probably including H-bonding and π-π interactions (Scheme 1B, structure III). The detection of all the protons from dopamine and DHI species in 1 H ss NMR spectra confirmed the non-covalent character of the interactions involved in this complex. However, it was observed that the dissociation of this complex leads to covalent bondforming oxidation reactions resulting in the formation of a 2,2' linked DHI-DHI dimer which eventually reacts with dopamine to form a covalent dopamine-DHI-DHI oligomer (C5 of dopamine connected to C4 of DHI). Thus, the authors suggested an overall mechanism for polydopamine formation implying two different pathways, (i) the self-assembly of dopamine and DHI to generate the physical trimer [(Dopamine) 2 /DHI], along with (ii) covalent bonds formation yielding structures like dopamine-DHI-DHI conjugates. More recently, these authors have reported the first experimental evidence that cation-, a non-covalent interactions mode unexplored so far in polydopamine materials, can be the driving force responsible for oligomers molecular assembly into polydopamine granules [121]. Such interactions were demonstrated to occur between protonated amines of uncyclized dopamine moieties and the -system of indole species leading to highly cohesive polydopamine structure (Scheme 1B, structure IV).

Co-contribution of covalent polymerization and non-covalent self-assembling

The aforementioned studies, among multiple others, highlighted that non-covalent interactions would play an important role in polydopamine assembling. So far, the general consensus favors the contribution of oxidative polymerization leading to covalent oligomers with different molecular weights, as well as the non-covalent interactions probably taking place in the latest stages of polydopamine synthesis, to yield the final insoluble polydopamine product. One of the most accepted models concurring with this theory, is the one illustrated by Liebscher et al. [123] who re-examined the major structural features present in PDA, using an association of a broad range of analytical techniques, including 1 H and 13 C ss NMR under magic angle spinning (MAS) conditions, electrospray ionization high-resolution mass spectrometry (ES-HRMS) in addition to XPS and FTIR. Their spectra interpretation revealed the presence of indolic moieties along with open-chain aminoethyl containing compounds and enabled the assignment of each C-atom to a moiety to which it belongs. Interestingly, it was observed that the two carbon lines at positions 4 and 7 cannot both be protonated, which was in disagreement with what was postulated by Dreyer et al. [119]. In matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), the peaks detected were attributed to oligomers composed of uncyclized dopamine and DHI-related units present under different degrees of (un)saturation and/or oxidation states, which concurred with the NMR and XPS results. The covalent connections between building units were proposed to occur via the benzo moieties yielding a linear hetero-polymer (Scheme 1B, structure V). In this model, the contribution of weak interactions was not excluded and was proposed to give rise to a supramolecular assembly of the linear PDA chains. Additionally, their DFT results implied a linear oligomeric chain structure for polydopamine and the stacking between PDA chains was revealed thermodynamically favorable and H-bonds were very likely to occur. Very recently, evidence for the PDA polymeric nature was provided by Messersmith's group [124]. By means of single molecule force spectroscopy (SMFS), the authors could demonstrate directly, for the first time, the presence of high molecular weight polymer chains. So far, the mass spectrometry methods allowed the identification of low molecular weight oligomers (up to the octamer level) [123,125,[129][130]. The SMFS technique, which enables the study of covalent and non-covalent interactions occurring at the scale of an individual macromolecule, was employed in this study to investigate polydopamine intermolecular and intramolecular interactions. PDA-coated AFM cantilevers were approached to then retracted from PDA coated or uncoated substrates. The analysis of the Force-distance curves obtained revealed the existence of constant force plateaus separated by "steps". The plateaus reflected the entropic resistance to polymer chain extension originating from a single molecule stretching event and the steps were related to the rupture of the connections in one or more PDA chains. Steps heights between the plateaus corresponded to the magnitude of the interaction's force. By analyzing these plateaus lengths, the authors could investigate PDA chains lengths and their molecular weights. Their results corresponded to a polydisperse polymer having an average molecular weight value of 11.2 kDa with some polymer chains having above 50 kDa. The great resistance of PDA polymer to very high forces that exceed the threshold of rupture for non-covalent interactions was consistent with a polymeric nature where dopamine and its oxidation derivatives are linked together linearly via aryl-aryl covalent coupling, in a manner similar to that proposed by Liebscher et al. [123]. However, the authors do not rule out the presence of small oligomeric species in PDA nanomaterials and stated the possible contribution of weak intermolecular interactions between PDA molecules to yield the final polydopamine materials.

Non-linear covalent oligomeric blocks and other building units were also proposed in polydopamine formation. For instance, beside phenylethylamines, indoles and indolines species listed so far, two pyrrolecarboxylic acids (PCA) were recognized for the first time by Della Vecchia et al. as building units of the polydopamine matrix [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]. The authors conducted a set of chemical and spectroscopic experiments, which enabled them to conclude that PDA is rather a mixture of oligomeric building blocks, up to the tetramer level, composed of three main species: uncyclized dopamine or its quinone-derivative monomers, DHI units and pyrrolecarboxylic acid moieties. These latter are likely to derive from partial oxidative cleavage of DHI units under the auto-oxidative conditions related to PDA formation process.

Similarly, Ding et al. [130] indicated the presence of a major mass peak at m/z 402, identified as a trimer complex consisting of two DHI units and one pyrrolecarboxylic acid moiety [(DHI) 2 /PCA] (Scheme 1B, structure VI); further covalent linkage between these trimers was found to be unlikely. More recently, Luy et al. [129] speculated that the peak at m/z 402 would correspond to a covalent trimer composed of one dopaminechrome (DAC), one DAC degraded unit (2H-pyrrole moiety) and one benzazepine moiety (Scheme 1B, structure VII). It could be noticed that such complex resembles to the dopamine/DHI/PCA-based models reported in the literature [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]130] and may share physico-chemical properties, allowing the authors to confirm its likelihood. All these authors proposed that covalent interactions occur at the initial stages of the polymerization process, leading to these small blocks, which interact in later stages via non-covalent interactions to build up the supramolecular structure of PDA.

In line with the previous findings, Warren's group studied by means of pump-probe microscopy the role of aggregation in polydopamine nanoparticles assembly [134] and suggested that polydopamine nanostructures result from the formation of covalent fundamental oligomeric blocks that stack together via non-covalent interactions, mainly - stacking, to form stacked oligomers, also known as "protomolecules". These stacked oligomers would further aggregate leading to the hierarchical self-assembled structure of polydopamine particles.

Multiple other scenarios regarding dopamine polymerization were proposed in the literature, sometimes without sufficient experimental evidence. As an example, porphyrin-like cyclic tetramers for example can result from oxidative polymerization of DHI units and were indeed found in eumelanin materials (Scheme 1B, structure VIII) [131]. Such compounds were identified as the most stable tetramer generated from oxidized DHI units using the computational structural investigation elaborated by Chen et al. [126].

To summarize, numerous models have emerged concerning polydopamine key components and its buildup mechanisms. However, it is currently agreed that these models should not be considered as mutually exclusive, since polydopamine is very likely to result from the combination of various mechanisms occurring at different stages of the polymerization process, as stated earlier.

Physico-chemical properties of polydopamine nanostructures and their implementation in cancer treatment

Polydopamine products display multiple characteristic features arising from their chemical and structural resemblance to naturally occurring eumelanin. The investigation and interpretation of the physico-chemical and functional properties of polydopamine materials were indeed often made in analogy to their natural counterparts to allow a better understanding of their common features. It is important to note however, that PDA nanomaterials properties are highly dependent on their preparation method and may particularly vary when polymerization is achieved in presence of additives that risk interacting with or be entrapped within polydopamine matrix.

Toxicity, Biocompatibity and Biodegradability

Based on structural and physico-chemical similarities reported between synthetic eumelaninlike polydopamine and naturally occurring melanin, polydopamine materials were anticipated to benefit from the wide distribution of melanin in the human body and show excellent biocompatibility [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF][START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. Numerous in vitro and in vivo studies performed on PDA-based nanosystems (PDA nanospheres, PDA nanocapsules, PDA-coated nanoparticles) confirmed their biocompatibility and revealed their great potential as candidates for in vivo biomedical applications. However, the presence of dopamine monomers in polydopamine matrix, as revealed in some reports [120], have raised questions regarding the possible cytotoxic effects that could be related to this neurotransmitter. To address this issue, Hong et al. examined the amount of dopamine released from PDA particles. Their findings revealed an extremely lowlevel release of dopamine, which was attributed to a robust self-assembled structure in which dopamine is well-entrapped. Cytotoxicity assays showed a viability maintained to > 90 % with preserved growth and morphology [120], which was consistent with the excellent biocompatibility of polydopamine widely documented in the literature. Indeed, PDA-based nanosystems showed negligible toxicity on a wide set of cells tested in vitro (epithelial cells, endothelial cells, fibroblasts, osteoblasts, neurons, etc.), for which viability and proliferation ability were almost maintained to normal [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF][135][136]. In agreement with these in vitro assays, in vivo studies confirmed the excellent biocompatibility of PDA-based nanosystems used in various contexts [137][138]. For instance, PDA nanoparticles injected intravenously in rats showed a very low acute toxicity with a very high median lethal dose (about 500 mg/kg), nearly five hundred times the dose used for their photothermal therapeutic applications.

Interestingly, long-term in vivo toxicity monitored over a one-month period after a single intravenous injection in mice or rats revealed that the animals remained healthy with no sign of behavior abnormalities; complete blood panel tests showed normal biochemical indicators with no detectable interference with the physiological regulation or immune response.

Moreover, the histopathological examination did not show any sign of tissue damage, inflammatory, or fibrosis aspect with no detectable change in the cellular structures [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF][START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF]. These findings were in line with the results reported for melanin showing no noticeable toxicity detected within 30 days, after injection of high doses (up to 100 mg/kg) in mice [139]. Furthermore, multiple evidences indicated that polydopamine coatings, shown to be ultra-stable in vivo, can interestingly function as a biocompatible layer allowing to significantly attenuate the intrinsic toxicity of biomaterials in a material-independent manner. Indeed, several reports have highlighted the beneficial role of PDA coatings in reducing the inflammatory and immunological side responses and improving the biocompatibility of various materials including organic materials (like poly-L-lactic acid), metallic nanoparticles (like gold nanoparticles), quantum dots, etc. [START_REF] Liu | Mussel-Inspired Polydopamine: A Biocompatible and Ultrastable Coating for Nanoparticles in Vivo[END_REF][140][141][142]. PDA coatings also showed a beneficial role in promoting hemocompatibility and controlling cell adhesion and proliferation on substrates [143][144]. Increasing the hydrophilicity of the tissue-contacting interfaces was proposed as an important factor responsible for the reduction of the in vivo side responses in PDA-coated biomaterials in contact of tissues or blood.

Beside their high biocompatibility, several findings reported in the literature led to the identification of polydopamine as a biodegradable material. Its naturally occurring analogue, i. e. eumelanin, is assumed to be metabolized in vivo, although the exact biodegradation pathways are not fully known yet. Langer's group revealed that synthetic melanin implants could be significantly resorbed within 8 weeks, which was attributed here to an uptake of melanin particles by macrophages and giant cells and to a further intracellular degradation process [145]. In fact, it has been demonstrated that both polydopamine and natural melanin undergo a hydrogen peroxide-mediated decomposition related to the oxidative cleavage of oquinone-indole moieties leading to the formation of pyrrole-2,3-dicarboxilic acids (PDCA) or pyrrole-2,3,5-tricarboxylic acids (PTCA), depending on branching positions in covalent oligomers [START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF][START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. This observation is highly interesting for the understanding of the possible biodegradation process of polydopamine, since hydrogen peroxide and other reactive oxygen species are endogenous components that can be produced majorly by NADPH oxidases, which are enzymes largely distributed in phagocytes and many organs [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF][START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]146]. This oxidation-induced process is generally accepted as a likely degradation pathway of polydopamine materials in vivo.

These intrinsic biocompatibility and biodegradability of polydopamine materials make them highly suitable for in vivo applications.

Nanomechanical properties

Nanomechanical properties of biomaterials and drug delivery systems are key parameters that influence their biological performance. In particular, nanoparticles elasticity has been recognized to play an essential role in directing nanoparticles biodistribution through impacting their blood circulation, tissue penetration, cell internalization, etc. [147][148][149]. The evaluation of nanoparticles mechanics is also of great interest for the understanding of their structural and functional properties. However, in the case of polydopamine nanomaterials, only few studies have dealt with the evaluation of polydopamine mechanical behavior, but were limited to PDA films and coatings. Mechanical studies performed on conventional polydopamine coatings revealed relatively high Young's modulus values of few GPa (~ 2 GPa to ~ 4 GPa), as measured via AFM nanoindentation or compressive film buckling experiments [150][151][152]. Such elasticity can reflect the good cohesion of polydopamine nanostructures and the ultra-stability of PDA coatings in vivo. Films elasticity was also investigated using computational approaches. DFT simulations using models based on dimers of dopamine, dopaminochrome and DHI units predicted Young's modulus values ranging from 0.33 to 1.24 GPa, depending on molecules directions [150], while other in silico models generated from controllable covalent cross-linking of DHI units provided Young's moduli comprised between 4.1 to 4.4 GPa for the highest covalently cross-linked polymer model ( 70%) [152]. Interestingly, increased elastic moduli could be obtained by increasing the inter-unit bonding in silico, suggesting that it is possible to enhance the mechanical strength of PDA materials through increasing the polymerization extent. Indeed, knowing that ~ 20 % of polydopamine structure is composed of unpolymerized monomers or partially polymerized oligomers, several relevant experimental studies demonstrated that increased robustness and enhanced mechanical performance of PDA coatings could be achieved through techniques allowing the enhancement of polydopamine cross-linking level and impacting eventually its cohesive structure. For example, the addition of copper ions [151], calcium cations or crosslinkers like genipin [150], heat treatment (up to 600 °C) inducing PDA carbonization [151], or thermal annealing at moderate temperatures (~ 130 °C) [153] resulted in increased Young's modulus values and allowed the production of highly stable PDA coatings resistant to delamination and dissolution, usually occurring under strong alkaline conditions for example.

Controlling the experimental conditions of polydopamine synthesis and post-processing methods has thus a great impact on the mechanical properties of PDA materials and consequently on their stability and biological fate, but would considerably impact their physico-chemical properties.

Since it is generally accepted that polymeric nanomaterials would behave differently from their bulk counterparts, the investigation of the nanomechanical properties of PDA nanoparticles is of great interest for a better comprehension of their structural characteristics, but the first report investigating PDA nanoparticles nanomechanical properties has only been published very recently by our group [START_REF] Zmerli | Bioinspired polydopamine nanoparticles: synthesis, nanomechanical properties, and efficient PEGylation strategy[END_REF] (Figure 4). In this study, we have evaluated the elasticity of polydopamine nanospheres and examined the impact of nanoparticles size on their Young's modulus, using AFM nanoindentation method. Interestingly, we found that the elastic modulus exhibited by PDA nanoparticles depended on their size, with average values of 188±42 MPa, 313±76 MPa, 365±59 MPa and 480±108 MPa for nanoparticles having average hydrodynamic diameters of 106±2 nm, 131±2 nm, 161±2 nm and 290±2 nm, respectively. The increased elasticity obtained when the nanoparticles size increases could be interpreted by the geometric packing order model described in details in the section 4.4.

Indeed, based on this model and on pump-probe microscopy analyses, Warren's group [134] suggested that bigger polydopamine nanoparticles would have higher geometric packing order between the stacked oligomers forming the core of the nanoparticles, which could interpreter the higher Young's modulus obtained for bigger nanoparticles in our study. Compared to other polymeric nanosystems such as PMMA, PS and PLGA nanoparticles, PDA nanoparticles showed Young's moduli of about one order of magnitude lower. This difference may be attributed to the different structures, intra-particulate interactions and assembly modes, and would be expected to correlate with a better biological performance, owing to less macrophages uptake and greater tumor accumulation [148][149].

Polydopamine chemical reactivity

As detailed in section 3, polydopamine is composed of heterogenous building units, which expose various reactive sites prone to a wide set of covalent, non-covalent and coordinate couplings with different types of materials and molecules (Figure 5) [START_REF] Ryu | Polydopamine Surface Chemistry: A Decade of Discovery[END_REF]. The catechol and amine functions, abundant in polydopamine, have been recognized as key features responsible for the high reactivity and strong adhesion of this material [154]. The major interactions reported for polydopamine adhesion mechanism and its reactivity will be discussed below.

Adhesive properties

Polydopamine is the first reported material that can strongly adhere to virtually all types, shapes and sizes of substrates, including noble metals, oxides, polymers, semiconductors, ceramics, low energy surface materials and superhydrophobic surfaces, etc. [START_REF] Lee | Mussel-Inspired Surface Chemistry for Multifunctional Coatings[END_REF][START_REF] Ryu | Polydopamine Surface Chemistry: A Decade of Discovery[END_REF]. It can interestingly form a firmly adherent layer likely owing to numerous extremely close anchoring points, which can be used to coat porous materials including metal organic frameworks (MOFs) and mesoporous nanostructures usually difficult to coat [START_REF] Lee | Material-Independent Surface Chemistry beyond Polydopamine Coating[END_REF]. This strong interfacial adhesion allowed the design of diverse core@PDA shell nanocomposites (inorganic or organic nanoparticles, liposomes, etc.) in which the polydopamine layer, highly stable in vivo, can be used to enhance biomaterials biocompatibility, serve as a bridge for secondary functionalization steps, or also be used for its therapeutic or theranostic potential as will be described later. Table 2 illustrates few examples of PDA-coated nanoparticles applied in cancer therapy and the role of PDA shell in the cited systems. Imaging-guided PDT [78] Silica NPs (Mesoporous NPs) PLGA: poly(lactide-co-glycolide), TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate, PEG: polyethylene glycol, 5-FU: 5-fluorouracile.

This unique property is most likely the result of an interplay of chemical interactions involving two vital motifs present in polydopamine, i. e. catechol and amine functions, which represent also the major functionalities present in mussel adhesive proteins [START_REF] Ball | Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings Biointerphases[END_REF]165]. Various covalent and non-covalent interactions can be engaged depending on the surface to coat. The catechol function is able to interact with a wide variety of substrates mainly via coordination bonding, bidentate chelating or bridged bonding and hydrogen bonding, etc. [START_REF] Ye | Bioinspired catecholic chemistry for surface modification[END_REF]166]. More recently, the primary amine group has gained increasing attraction in the understanding of polydopamine strong adhesion. The vital role of primary amines was highlighted by Klosterman et al. who revealed that the addition of primary amines while forming polydopamine coatings increased this latter's adhesion properties [150]. Another evidence was brought by the observations revealing that mature particles do not exhibit a high adhesion capacity to surfaces, which was ascribed to the fewer amount of primary amines [25,[START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF], in comparison to the strong adhesion obtained when surface coating is performed during the early stages of polydopamine formation [25,[START_REF] Vecchia | Buildingblock diversity in polydopamine underpins a multifunctional eumelanin-type platform tunable through a quinone control point[END_REF]. Besides, it was found that poly(catecholamine) coatings exhibited a significantly higher adhesive strength (30-times) than that of poly(catechol) ones [154]. These findings suggest that polydopamine coatings grow progressively from the surface of the coated structure and the high cooperative adhesive action of these functional groups contribute to the resulting cohesive stable layer.

Metal binding ability

Catechol function is the major responsible of PDA affinity to several metal cations, including Fe 2+ , Fe 3+ , Cu 2+ , Mn 2+ , Pb 2+ and multiple others. It can indeed strongly bind to multivalent metal cations through the o-diphenol functionality, and it exhibits a higher binding affinity compared to o-quinone [167]. This chemistry depends however on several conditions including the pH [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF] or the affinity of catechol towards the metal ion. It should be noted that other functional groups present in polydopamine would also participate in metal chelating properties, such as amine, carboxylic and phenolic groups [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. The polydopamine-metal coordination ability was explored for the preparation of diverse metal-organic frameworks (MOFs) [168][169][170] and has been considered of particular interest for the design of novel PDAbased theranostic systems. For instance, several magnetic resonance imaging (MRI)-guided nanoplatforms have been described in tumor imaging and were obtained through interaction of polydopamine with paramagnetic metal ions like Gd 3+ [171], Fe 3+ [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF] or Mn 2+ [172],

leading to efficient MRI contrast nanoagents exhibiting high longitudinal relaxivity values in comparison to conventional contrast agents [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. Such theranostic systems could be in fact achieved either by loading/anchoring the metal cations onto PDA nanostructures [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF]173] or via coating metal oxide cores (like Fe 3 O 4 or Mn 3 O 4 ) with a PDA shell [138,174].

It was found that the chelation of metal ions would induce their reduction and subsequent transformation into metallic nanoparticles bound to PDA surface, this was used for the in situ growth of Au [175] or Ag [176] nanoparticles on polydopamine surface. In addition, the catechol reactivity towards metal cations has been largely explored in polydopamine synthesis process as described in the section 1 and could be also used for the complexation of deassembled PDA aggregates as a strategy to form cohesive robust PDA coatings [177].

Furthermore, it has been recently discovered that polydopamine nanoparticles can selectively kill cancer cells through a ferroptosis mechanism involving this metal complexation ability [135][136]. In vivo, biological melanins are also well-known for their affinity towards metal ions [178], which is used for instance for the sequestration of potentially cytotoxic transition metals [START_REF] Xie | Natural Eumelanin and Its Derivatives as Multifunctional Materials for Bioinspired Applications[END_REF].

Chemical reactivity

The high chemical reactivity of polydopamine is particularly interesting for the design of multifunctional nanosystems and can serve to extend polydopamine nanomaterials applications.

Covalent interactions

Catechol / Quinone reactivity (Figure 5A,B)

The catechol group, a central element in polydopamine reactivity, is in fact present in a chemical equilibrium with its corresponding quinone [START_REF] Ball | Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings Biointerphases[END_REF], and the reduced/oxidized state of the catechol/o-quinone system is of great importance to direct polydopamine reactivity. This equilibrium can be impacted by the solution pH, the presence of oxidants/reductants, or by exposition to relatively high temperature under air.

O-quinone systems, owing to the carbonyl function and Michael acceptor character, are prone to addition reactions of nucleophilic groups such as thiols and amines, via Michael addition (for thiols and amines) or Schiff-base condensation (for amines). The most favorable positions for such addition reactions depend on the type of the engaged nucleophile and on the quinone system (dopamine-quinone or indole-quinone). For instance, Michael addition of thiols or amines occurs preferentially via 1,4-addition while carbonyl reactivity with amines is preferentially a 1,2-addition type yielding the Schiff-base [25]. This chemistry is one of the most explored strategies used for the immobilization of (bio)molecules, such as polymers [179][180], proteins [181][182] or small molecules [183], on the surface of polydopamine nanoparticles or shells (Table 3). This is mainly attributed to its simplicity (since the reaction can be simply conducted under mild alkaline aerobic conditions) and to its versatility (since amines and thiols are present in numerous molecules or can be easily introduced into them) [25]. Poly(ethylene glycol) (PEG) chains grafting is for instance often achieved using this oquinone reactivity, allowing the formation of a hydrophilic antifouling coating on the surface of polydopamine nanoparticles or PDA-coated nanosystems, permitting to improve their colloidal stability, reduce their uptake by the reticuloendothelial system and prolong their blood circulation times [START_REF] Amin D R | Size Control and Fluorescence Labeling of Polydopamine Melanin-Mimetic Nanoparticles for Intracellular Imaging Biomimetics[END_REF][184][185]. Also, tumor targeting molecules like folic acid [186],

galactosamine [187] or EGFR antibody [188] could be grafted on PDA surface via this chemical route, in order to improve tumor accumulation for enhanced treatment efficiency and reduced side effects [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. Few examples of the implementation of this chemistry are illustrated in table 3.

Polyethyleneimine (PEI)

In situ formed polydopamine nanoparticles --Co-polymerization of dopamine and PEI for the preparation of fluorescent polydopamine nanoparticles, through the reduction of - interactions [192] NPs: nanoparticles, NCs: nanocapsules Amine reactivity (Figure 5C)

In addition to the catechol/o-quinone system, the amine groups also contribute to the chemical reactivity of polydopamine through interaction with electrophilic moieties or exhibiting an acid/base reactivity [25]. For instance, amine functions present in PDA can interact with carboxylic groups to form an amide function via conventional carbodiimide chemistry reported as a drug coupling strategy [193], or serve as a reactive site for facile coupling of isothiocyanate-containing molecules that can be particularly used for PDA nanoparticles labelling. Moreover, an amine-mediated acylation reaction was employed to immobilize an ATRP initiator on PDA-coated particles allowing for a surface-initiated polymerization and controlled growth of polymer brushes from the particles surface [194]. Amines are also involved in aza-Michael-type addition which was used for polydopamine functionalization using acrylate/acrylamide molecules [195].

Non-covalent interactions (Figure 5B, D)

Due to the presence of catechol groups and pyrrolcarboxylic acids (acidic) on one hand and amines groups (basic) on the other hand, polydopamine displays a zwitterionic character with an isoelectric point of ~ 4 [START_REF] Amin D R | Size Control and Fluorescence Labeling of Polydopamine Melanin-Mimetic Nanoparticles for Intracellular Imaging Biomimetics[END_REF]196]. Polydopamine can hence expose positive or negative charges depending on the medium's pH. This functionality was explored for the highly selective pH-responsive uptake and release of charged small molecules into PDA capsules [196], and represented an interesting approach for controlled drug loading and release in the drug delivery applications.

Beside electrostatic interactions, polydopamine assemblies are able to interact with diverse molecules through other non-covalent interactions, namely - stacking, hydrophobic effects and Van der Waals interactions and H-bonding. Indeed, the abundance of -conjugated, aromatic and phenolic structures in polydopamine network allowed for multiple drugs, including doxorubicin [START_REF] Xing | Mesoporous polydopamine nanoparticles with codelivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy[END_REF]197] and paclitaxel [198] or photosensitizing molecules like chlorin e6 [199] and indocyanine green [185,197], to be loaded in the polydopamine matrix [START_REF] Xing | Mesoporous polydopamine nanoparticles with codelivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy[END_REF]199] or bound onto polydopamine surface [197], affording thus PDA-based therapeutic platforms working as promising candidates for efficient cancer treatment.

UV-visible-NIR absorption properties

Unlike common organic products, synthetic eumelanin-like polydopamine displays a broadband absorption extending over the whole UV-visible-NIR regions, and increasing monotonically towards high energies [START_REF] Xie | Natural Eumelanin and Its Derivatives as Multifunctional Materials for Bioinspired Applications[END_REF]. This unique profile has been reported before as a characteristic optical feature for natural melanins (eu-, neuro-, allo-and pheo-melanins) [200][201][202]. The extinction coefficients calculated for the wavelengths ranging from 300 to 1000 nm for both polydopamine nanoparticles and melanin granules were found to be very close, especially for the smallest nanoparticles [START_REF] Amin D R | Size Control and Fluorescence Labeling of Polydopamine Melanin-Mimetic Nanoparticles for Intracellular Imaging Biomimetics[END_REF]. Based on these spectral similarities, analogies were made between the two resembling materials for a better interpretation of polydopamine optical properties. The "chemical disorder model" is accordingly one well-accepted explanation of this broad absorption band characterizing eumelanin and synthetic eumelanin-like materials, particularly polydopamine [202,204]. In this model, the monotonic absorption profile is the consequence of the overlapping of different absorption bands associated to ensembles of chemically distinct species present in the material network [202].

Although the chemical disorder model can be used for the understanding of the broad absorption, the structural complexity at the origin of such absorption can not only be related to the chemical heterogeneity at the level of fundamental building units but also to the hierarchical assembly configurations (at secondary/supramolecular level), which produce a wide series of Highest Occupied Molecular Orbital (HOMO) -Lowest Unoccupied Molecular Orbital (LUMO) gap energies, resulting in the monotonic featureless broad absorption band [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF]204]. In this context, few models have been suggested to interpret the unique absorption profile of natural or synthetic eumelanins. Indeed, the oxidation/reduction dynamics among eumelanin-like oligomers and the aggregation-dependent interchromophoric interactions were presented as important factors perturbing -electron delocalization [205][206], resulting in different HOMO-LUMO gaps. The oxidized forms were admitted to have lower HOMO-LUMO gap energy, thus leading to a broadening of eumelanin absorption band.

More recently, the geometric order / disorder model emerged as another key factor to consider in the interpretation of the broad absorption of eumelanin and polydopamine. The significant contribution of non-covalent interactions in the assembly process of polydopamine, including - stacking,-cation interactions and charge transfer, has been well-established using experimental and computational structural investigations. Since -electron density of eumelanin-like oligomers is an important parameter impacting their absorption profiles, the proximity between oligomers but also the packing between stacked oligomers would impact the absorption spectrum of the assembled structure [134,[206][207][208] originate from a multi-step process consisting in (i) the formation of oligomeric building blocks, (ii) their consecutive stacking followed by (iii) the aggregation of these stacked oligomers, the authors examined the absorption features at these different assembly levels (Figure 7). It was found here that low molecular weight (LMW) subunits present higher UV absorption compared to larger fragments, while high molecular weight (HMW) fractions showed an enhanced absorption at the visible and NIR wavelengths compared to LMW units.

A possible explanation suggested that HWM fractions would be composed of higher MW oligomers, leading to more extended -electron delocalization within oligomers and thus to a lower HOMO-LUMO gap energy. A higher stacking order between oligomers of different HOMO-LUMO gaps would enhance the absorption at low energies [134,209]. Interestingly, the authors revealed that HMW fragments exhibited different absorption behavior compared to their parental nanoparticles. This implied that a change in the electronic structure would occur when the stacked oligomers aggregated to form the nanoparticle. A size-dependent absorption was also found for PDA nanoparticles; larger nanoparticles displayed higher absorption at longer wavelengths compared to smaller ones. Based on these observations, Warren's group concluded that, in addition to the chemical diversity model and the fundamental oligomers' -electron delocalization, the geometric packing order of the protomolecules in eumelanin-like systems is a key determinant in the broad-band absorption of the final aggregated assembly; it may impact the interactions between oligomers changing thus the absorption behavior. The number of stacked oligomers would impact the geometric preference, which results in the size-dependent absorption profiles. The higher absorption observed at longer wavelengths for large nanoparticles in comparison to smaller ones was also reported by Wang et al. [96]. It should be noted, that the geometric packing order model detailed by Warren's group is well-adapted to interpreter the size-dependent properties of PDA nanoparticles, namely the nanomechanical [START_REF] Zmerli | Bioinspired polydopamine nanoparticles: synthesis, nanomechanical properties, and efficient PEGylation strategy[END_REF] and photothermal properties [START_REF] Wang | Size control synthesis of melanin-like polydopamine nanoparticles by tuning radicals[END_REF], as will be discussed later.

Fluorescence emission properties

An investigation of the absolute radiative quantum yields of synthetic eumelanin was performed by Meredith et al. and showed that more than 99.9 % of the absorbed light in the UV and visible regions was dissipated through non-radiative relaxation mode [210], which concurred with previously reported findings revealing an extremely low emission quantum yield ( r as low as 0.003) [211][212]. Comparably to other synthetic eumelanins, very weak emission spectra were reported for conventionally-prepared polydopamine nanoparticles [213]. Similar to self-assembled organic chromophore systems, the stacking of fundamental oligomers and the subsequent aggregation in PDA nanomaterials were proposed to be at the origin of the observed self-quenching effects [213].

Interestingly, although very weak, the emission of synthetic eumelanins showed a clear dependency of the position, width, intensity and quantum yield on the excitation energy, which is an uncommon feature for organic materials. Lower excitation energies led to lower radiative emission, with for example a four-fold increase of the quantum yield at a 250 nm excitation compared to 500 nm [210,214]. A 3D map of specific quantum yields variation as a function of excitation and emission wavelengths was developed to help understand the photophysical and structural properties of eumelanin-like materials [214]. The photoluminescence was proposed to arise from different HOMO-LUMO gap energies related to oligomers of chemically distinct species, supporting hence the chemical disorder model described above [210]. This hypothesis was supported in other reports which related eumelanins emission properties to the chemically distinct oligomeric units that can be selectively excited at different excitation wavelengths [214][215]. These interpretations can be also applied to polydopamine [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF].

Furthermore, size-dependent emission spectra and yields were obtained for eumelanin samples [211]. The small eumelanin aggregates exhibited higher emission yields with longer emission decay times (> 1 ns for < 1000 Da) compared to larger ones (< 1 ns for > 10000 Da).

Also, it was found that energy transfer occurs both within but also between the fundamental building units. Thus, the aggregation state, responsible for eumelanin-like materials buildup, was proposed as another determinant factor in this photophysical property [211][212].

Interestingly, several groups have shown that fluorescent polydopamine nanomaterials can be made by tailoring polydopamine synthesis or post-processing conditions. Endowing polydopamine products with luminescence properties can be indeed of great utility for the development of nanosystems used in medical imaging or fluorescence bioimaging-guided therapies. Different fabrication strategies have been developed in order to achieve the desirable photoluminescence properties of polydopamine and were categorized, by Yang et al.

Photothermal and Photoacoustic properties

Due to their intrinsic fluorescence self-quenching effect, polydopamine products are able to generate heat when they are photo-excited. This is because the repopulation of the ground electronic state occurs predominantly through non-radiative relaxation and the majority of the absorbed energy is released as heat via vibrational relaxation [START_REF] Ball | Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings Biointerphases[END_REF]. Indeed, a transient pumpprobe analysis performed on eumelanin-like samples showed a very rapid ground-state bleaching with about 90 % of the absorbed energy dissipated as heat, within a relaxation time of 20 ps [212].

This characteristic feature, together with the broad light absorption band, paved the way for the eumelanin-like polydopamine nanomaterials to be investigated as potential agents used in hyperthermia-mediated therapy called "photothermal therapy" (PTT). This therapeutic approach is in fact based on the administration of a light-heat converting agent followed by the illumination of the targeted site with a localized laser. The heat generated locally by the photothermal agent, upon its photo-excitation, is used to kill abnormal cells nearby. PTT has been largely explored in the past years as a minimally invasive therapeutic method showing promising results in efficient tumor ablation, but also in other applications such as multiresistant bacterial infections treatment. This method is recognized as a particularly advantageous treatment modality, compared to the conventional cancer therapies owing notably to the spatio-temporal controllability which allows improved target selectivity and minimal side effects, with subsequent efficiency enhancement [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. The photothermal agents currently available are mainly consisting in metallic nanoparticles, particularly Au nanoparticles, and few carbon-based nanosystems. However, these nanoagents usually suffer from long-term biosafety, compromising their clinical implementation [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. The application of biocompatible and biodegradable materials in photothermal therapies is hence of great interest for the in vivo biomedical applications.

Liu et al. have introduced, for the very first time, melanin-like polydopamine nanoparticles as a powerful photothermal agent fulfilling all the requirements for an in vivo PTT application [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. Colloidal PDA nanospheres displayed a strong NIR photo-absorption, with a molar extinction coefficient of  808 nm = 7.3 10 8 M -1 .cm -1 (for a nanoparticles size of 70 nm), which is relatively high in comparison to values reported for multiple photothermal agents such as carbon nanotubes ( 808 nm = 7.9 10 6 M -1 .cm -1 ) [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. A strong absorption in the so-referred-to "photo-therapeutic window" (650 nm -850 nm) is in fact highly interesting for clinically relevant photothermal applications. In this optical window, there is a minimal interference of biological chromophores absorption or scattering effects and a maximal penetration depth of the incident light is enabled [START_REF] Cheng | Versatile Polydopamine Platforms: Synthesis and Promising Applications for Surface Modification and Advanced Nanomedicine[END_REF]223].

The photothermal conversion efficiency is another key parameter indicative of the photothermal agents' efficiency. In the case of PDA nanospheres of 70 nm, the photothermal conversion efficiency was found to be about 40 % [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. This value is interestingly high compared to the most common PTT agents, such as gold nanorods, widely reported for cancer treatment, which exhibit a photothermal conversion efficiency of 22 % [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF]. Indeed, upon 500 s of illumination with an 808 nm laser at 2 W.cm -2 , these PDA nanospheres dispersed at 200 µg/ml induced a temperature increase of the suspension of almost 34 °C. This result is very satisfying for high-temperature hyperthermia-mediated tumor ablation, since it is accepted that cancer cells, which are more sensitive to hyperthermia than normal cells [224], can be killed when the surrounding temperature increases to values > 50 °C for 4-6 minutes, or 42-45 °C for 15-60 min [225].

These findings were later confirmed by several groups who reported a temperature increase of a similar order of magnitude. The generated temperature increased in a concentration-and laser power-dependent manner [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF][START_REF] Xing | Mesoporous polydopamine nanoparticles with codelivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy[END_REF]193,[226][227]. Similar to the colloidal nanospheres, multiple PDA-based nanostructures, such as PDA shells [228][229][230], polydopamine dots [231] and mesoporous polydopamine nanostructures [232], showed excellent photothermal properties relevant to polydopamine nanostructure. In the case of core@PDA shell systems, an improved photothermal effect could be obtained by increasing polydopamine shell thickness [228][229].

Although the photothermal properties of polydopamine materials have been demonstrated by several groups, a full understanding of this photothermal conversion ability is still lacking.

Particularly, to the best of our knowledge, no work has yet studied in depth the impact of PDA nanoparticles size on their photothermal conversion efficiency. In one recent study, Wang et al. have briefly revealed a dependency of the solution temperature increase on the size of PDA nanoparticles; larger nanoparticles induced higher temperature increase compared to smaller ones. This result was attributed here to the higher absorption in the NIR region (808 nm) observed for larger nanoparticles [START_REF] Wang | Size control synthesis of melanin-like polydopamine nanoparticles by tuning radicals[END_REF]. A similar result was also reported for mesoporous polydopamine nanoparticles [232]. These findings could be interpreted by the geometric packing order / disorder model and the aggregation state of the stacked oligomers forming PDA nanoparticles, as explained before: bigger polydopamine particles would exhibit a higher geometric packing order [134], and thus higher excitonic effects, NIR absorption and quenching effects, leading to the stronger heat generation.

Interestingly, when PDA nanoparticles were subjected to a long-time laser illumination (2 W.cm -2 for 1 h) [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF][START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF] or repeated illumination-cooling cycles (up to five cycles) [189,226] they showed a high photo-stability as evidenced by the stable temperature increase obtained at the different cycles, by the stable absorption features and by the absence of morphological changes before and after illumination. Such property is crucial for the maintenance of efficient light absorption during NIR irradiation, and renders polydopamine-based nanostructures superior to gold nanoparticles, largely reported in PTT applications, which undergo morphological changes resulting in decreased light absorption during NIR activation [START_REF] Liu | Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for In[END_REF].

The excellent photothermal stability during cyclic irradiation, along with the strong light absorption and great photothermal activity and conversion efficiency, suggested that PDA nanoparticles would be of a great potential in photoacoustic imaging (PAI) applications. This technique is in fact an emerging bio-imaging method allowing to dynamically monitor the biodistribution and tumor retention of injected systems and offering a high tissue penetration depth, spatial resolution and sensitivity. It relies on pulsed illumination of a photo-thermal converting agent, the heat generated by this latter would thermo-elastically generate pressure waves detected using an ultrasound transducer [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]233]. The combination of photoacoustic and photothermal effects in a single system would be highly interesting for photoacoustic imaging-guided cancer photothermal therapy applications, offering hence a desirable theranostic platform [234]. Aqueous PDA nanoparticles suspensions exhibited a concentration-dependent photoacoustic performance and interestingly photoacoustic signals could be detected even at concentrations as low as 15 µg.ml -1 . In vivo assays revealed the excellent photoacoustic contrast generated by polydopamine nanoparticles and tumor-targeted PDA nanoparticles enabled significant illumination of the tumor site with a clear margins delineation. Several other studies followed and confirmed the great potential of polydopamine-based nanosystems for PAI applications [137,232,[235][236]. PDA-coated nanostructures were also proven to exhibit excellent photoacoustic properties. For instance, 200 nm-sized PDA hollow nanocapsules dispersed at 200 µg.ml -1 exhibited a slightly higher photothermal conversion efficiency (40.4% versus 37.1%) and over two-folders higher photoacoustic imaging ability in comparison to PDA nanospheres of similar size and at similar concentration [START_REF] Zhuang | Polydopamine Nanocapsule: A Theranostic Agent for Photoacoustic Imaging and Chemo-Photothermal Synergistic Therapy[END_REF]. The higher photoacoustic signals were attributed to the higher photothermal conversion ability, but also to the hollow structure favorable for harmonic imaging enforcing the ultrasonic signals.

Application of PDA nanomaterials in cancer therapy

Drug delivery applications

The administration of free anti-cancer drugs usually encounters several limitations, including particularly solubility issues or a non-specific biodistribution leading to a poor drug bioavailability and severe side effects [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. In order to overcome these limitations, diverse drug delivery nanosystems have been developed with several successful clinical implementations, benefiting from their passive tumor accumulation via the EPR effect [237].

In this context, owing to its high chemical reactivity resulting in high drug payloads and its multi-drug loading ability, PDA-based nanostructures have received considerable attention as drug carriers allowing drug/gene delivery for efficient cancer treatment. Moreover, when the anti-cancer drug is physically loaded on the nanocarrier, the H-bonding and π-π interactions generally established between polydopamine and the loaded drugs tend to be disrupted or weakened under acidic, oxidative or also reductive conditions. Therefore, PDA nanostructures would benefit from the intrinsic tumor microenvironment characteristics (i. e. weakly acidic pH, high amounts of hydrogen peroxide and of glutathione) and function as stimuliresponsive drug delivery systems [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF]. Moreover, taking advantage of the endocytosismediated internalization process of PDA nanoparticles demonstrated by Ding et al. [238],

drug release can be triggered in the acidic endosomal and lysosomal compartments allowing the intracellular delivery of the anti-cancer drug. Additionally, the hyperthermia generated by polydopamine upon its NIR illumination could also be explored to achieve an on-demand NIR-triggered drug delivery, as a result of weakened interactions with the loaded drug under heat [239].

In view of such features, PDA-based nanomaterials have been largely explored as drug nanocarriers, few examples are cited in table 4. They showed excellent results in preventing the premature drug release during circulation and inducing enhanced release rates after tumor internalization, compared to pristine or other nanoparticles. PDA nanocapsules and mesoporous PDA nanoparticles are particularly promising candidates for drug delivery applications, owing to their high payload capacity [191]. Regarding the PDA-coated structures, polydopamine coatings can serve either as the drug nanocarrier composite [240],

controlling the thickness of PDA shell allows here to control the drug loading rate, or serve as a "gate keeper" for a controlled drug delivery, owing to its stimuli-responsiveness [241].

PDA-based nanomaterials were in fact not only applied for the delivery of chemotherapeutic drugs, but were also extended to antigen delivery for anti-tumor immunotherapy [181]. They have emerged also as nanocarriers for photosensitizing agents used in photodynamic therapy (PDT). CT: Chemotherapy, NPs: nanoparticles

Light-mediated cancer therapies

Considering their outstanding photophysical properties, their colloidal stability and their superior biocompatibility and biodegradability, polydopamine-based nanosystems are emerging as attractive photothermal converting and photoacoustic-contrast agents and gaining an increasingly growing interest for efficient tumor ablation in PTT-based cancer therapy.

Coupling PDA nanoparticles to photoactive molecules also known as photosensitizer, would present several advantages for cancer therapy. Indeed, PDA nanoparticles may play the role of nanocarriers of the photosensitizers with a high payload. Moreover, this enables the design of bifunctional light activated nanoplatforms with subsequent photothermal effect (PPT) and photodynamic effect (PDT). Such combination would allow a more efficient and synergistic treatment modality of cancer. In the following section, we will first introduce the photothermal therapy and photodynamic therapy, and then we will develop the various strategies that can be adopted for the design of PDA based nanoparticles with bifunctional PTT/PDT applications. In addition, the interests and limits of the bifunctional nanoplatforms in cancer therapy will be also emphasized and discussed.

PDA nanoparticles for photothermal therapy

Liu et al. demonstrated the high photothermal efficiency of PEGylated PDA nanoparticles in vitro and in vivo, on a colon cancer model [START_REF] Liu | Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment[END_REF]. Significant tumor growth suppression was obtained following NPs intravenous injection into SW620-bearing mice and illumination using an 808 nm laser at 1.3 W.cm -2 for 6 min.

Various strategies have been employed to further enhance the photothermal effects obtained with polydopamine for an improved therapeutic efficacy.

Light absorbing molecules like indocyanine green (ICG) or IR820, can act as "thermalenhancement agents" [246]. They would result in an increased NIR absorption and their association to PDA nanomaterials has been described in several studies and resulted in enhanced photothermal performance and therapeutic outcomes. For instance, the association of the FDA-approved photosensitizing molecule ICG with polydopamine has been investigated for PAI-guided photothermal cancer treatment [235,247]. The loading of ICG into polydopamine allowed to significantly increase the system's NIR light absorption, up to 13 times higher at 780 nm. In return, polydopamine quenched the fluorescence of ICG and prevented its photobleaching, and lead to an improved stability under its laser irradiation. The hybrid nanoplatform exhibited an amplified photothermal effect with a temperature increment exceeding 14 °C in presence of ICG in comparison to the pristine system (after illumination at 808 nm, 0.6 W.cm -2 for 5 min, 20 µg.ml -1 ), as well as an improved photoacoustic contrast (Figure 8). The nanosystem represented hence a promising phototheranostic nanoagent achieving a complete tumor suppression with a low laser density, as evidenced by in vivo experiments. (Printed with permission from [235] ).

The coupling of metal ions, like Cu 2+ and Mn 2+ , to PDA nanostructures allows not only to perform bio-imaging but also to achieve amplified photothermal effects [START_REF] Park | Recent advances in melanin-like nanomaterials in biomedical applications: a mini review[END_REF]248]. Cu 2+loaded PDA nanoparticles were proposed by Ge. et al. as an efficient MRI-guided therapeutic nanoagent [248]. Indeed, in presence of Cu 2+ , a four-fold increase in PDA nanoparticles molar extinction coefficient was obtained, accompanied with a significantly enhanced photothermal conversion efficiency reaching 54.8 % for CuPDA against 37.6 % for PDA nanoparticles of a similar size (51 nm). Laser irradiation of a 75 µg.ml -1 nanoparticles suspension at 808 nm and 3.5 W.cm -2 induced a temperature increase of 51.5 °C for CuPDA versus 42.2 °C for PDA nanoparticles. Interestingly, the nanocomposite displayed a pH-responsive release of copper ions allowing their efficient delivery in the tumor tissue. The released ions exhibited a synergistic chemotherapeutic cancer cells killing effect.

Enhanced photothermal effects could also be obtained through the combination of PDA nanostructures to other photothermal converting agents. In this perspective, PDA-Au nanohybrids represent promising materials that benefit from the plasmonic photothermal activity of gold nanosystems along with the interesting photothermal conversion properties of polydopamine. For instance, Wu et al. fabricated an injectable thermoresponsive poly(Nacryloyl glycinamide-co-acrylamide) hydrogel containing PDA-coated gold nanoparticles and the anti-cancer drug doxorubicin, and serving as a breast filler for efficient prevention of breast cancer recurrence [249]. This nanocomposite exhibited an intriguing photothermal activity arising from the combination of both gold nanoparticles and polydopamine coating.

Interestingly, a red shifting was observed in the gold nanoparticles absorption spectra upon modification with polydopamine, suggesting a higher photothermal efficiency. A pronounced temperature increase was obtained, with a T reaching 43 °C after a 5 min irradiation with a 808 nm laser at 2 W.cm -2 .

In another example, the biocompatible graphene oxide (GO) was utilized in association to polydopamine, owing to its "intrinsic high NIR light absorption" and photothermal conversion ability. It was suggested that polydopamine would restore a part of  conjugation in GO through the reduction of this latter, generating stable reduced GO (rGO), characterized by its higher NIR light absorption and enhanced photothermal activity. This association is thereby very suitable for PTT applications, explaining the interesting temperature increase revealed in several studies for the PDA/GO nanohybrids [188,235,250].

PDA as nanocarriers of photosensitizers for photodynamic therapy (PDT) applications

PDT is a potent light-based therapeutic modality clinically approved for cancer treatment

[251] and is based on the use of a photosensitizer (PS), a light-absorbing compound, which photo-activation at an appropriate wavelength, leads eventually to the generation of reactive oxygen species (ROS) that are cytotoxic. Indeed, following the PS administration, the near infrared (NIR) irradiation of the tumor site induces the photo-excitation of the PS to an excited singlet state. The excited PS can then re-gain its fundamental state either directly through fluorescence emitting or via conversion to a triplet state, a lower energy excited state, through an intersystem crossing. At this state, the PS can interact either with nearby substrates through electron transfer to eventually produce free radicals (type I PDT reactions) or with molecular oxygen through energy transfer to singlet oxygen that is highly cytotoxic [253]. In fact, with oxygen being crucial for the photodynamic effects, tumors extreme hypoxia represents a major mechanism of resistance to the photodynamic therapy. To bypass this bio-barrier, the corpuscular hemoglobin in this nanosystem was about ten-fold higher than that of natural RBCs, thanks to the abundant catechol functions present in polydopamine.

Beside its role as a drug carrier, the anti-oxidation property of polydopamine, which is ascribed to the strong anti-oxidation ability of polyphenols, allowed it to mimic the antioxidative enzymes in RBCs, preventing hence the oxidative degradation of oxygen-transporting hemoglobin. This platform demonstrated its high potential in inducing a strong PDT effect against normoxic or extremely hypoxic tumors leading to a complete tumor ablation. It can interestingly serve as a universal platform for other oxygen-involved therapies such as radiotherapy. In this perspective, beside serving as simple nanocarriers for PS, an increasing number of papers have demonstrated the great potential of PDA nanomaterials conjugated to PS in inducing enhanced therapeutic outcomes through photothermal and photodynamic effects respectively. Curiously, based on the broad absorption band of PDA, single-wavelength activation protocols were applied in several studies in this combinational therapeutic approach [199], which facilitates the illumination procedure by reducing the needed equipment, and would lead to enhanced therapeutic efficacy due to the synchronized PTT/PDT activities [START_REF] Liu | Melanin-Like Nanomaterials for Advanced Biomedical Applications: A Versatile Platform with Extraordinary Promise Advanced Science[END_REF].

Nevertheless, PDA activation for PTT usually uses longer wavelength irradiations (808 nm)

in comparison to conventional wavelengths used in PDT, which permits to reach higher photothermal conversion and a higher tissue-penetration depth and eradicate deeper tumoral tissues.

Scheme 2. Structures of photosensitizers used for the design of PDA-based nanoparticles for synergistic photothermal/photodynamic therapy.

Several PSs have been coupled (scheme 2) to PDA nanoconstructs for the development of PDA-based bifunctional nanoplatforms. This can be done by using various strategies of PS couplings depending on the therapeutical application. Indeed, the PS can be (i) loaded inside the PDA matrix, (ii) physically adsorbed on the surface of nanoparticles or (iii) covalently bound to their surface (figure 9). [199]. This strategy allowed to load unprecedently high amounts of Ce6 in the PDA-based nanocarrier and offered an enhanced cellular uptake (over 8-fold higher) with a sustained drug release up to 5 days. Under a single laser irradiation at 665 nm and at a relatively low power density of 250 mW.cm -2 , this nanosystem showed improved additive cell killing effects in comparison to PTT or PDT alone.

Due to the fluorescence quenching and ROS scavenging abilities of polydopamine [START_REF] Liu | Polydopamine and its derivative materials: Synthesis and promising applications in energy, environmental, and biomedical fields[END_REF], the encapsulation of the photosensitizing drug in the core of the nanoparticles would prevent its degradation and limit its undesirable activation under day light. However, ROS generation and subsequently the anti-cancer photodynamic effect is only correlated to the amounts of released PS [199]; the unreleased PS remains inactive. Moreover, although this encapsulation strategy allows to preserve the surface properties of the nanosystem and despite the high PS loading amounts and the efficient drug delivery to the tumor, drug embedment in PDA matrix may induce changes in the stacking ang aggregation of PDA oligomeric building units, which would consequently impact the photophysical properties of PDA nanosystems and their nanomechanics, compromising hence their biological performance and therapeutic efficacy. Similarly, IR820, a NIR light absorber with a great potential in photodynamic and photothermal therapies but also in photoacoustic imaging, was used in association to polydopamine after being adsorbed on the surface of PEGylated PDA nanoparticles via - and electrostatic interactions [255]. The combination of both photothermal agents offered a considerable enhancement in the light-heat conversion efficiency of the nanoagent with a great photostability, which together with the ROS generation ability of the PS, IR820, allowed an efficient cancer treatment following a single laser irradiation at 808 nm with a power density of 1 W.cm -2 . Moreover, given the interesting PA properties of PDA nanoparticles and IR820, this system showed a great potential as a multifunctional nanoplatform for cancer theranostic applications.

A tumor targeting PDT-PTT platform was developed by Han et al. for improved therapeutic specificity and consisted in a novel photomedicine composed of a polydopamine core and a pheophorbide a-hyaluronic acid shell as an efficient anti-cancer agent displaying negligible side effects [256]. While hyaluronic acid acts as the tumor-targeting moiety, polydopamine acts as a quencher hindering the fluorescence and singlet oxygen generation of the conjugated PS. However, in the presence of cancer-specific enzymes, particularly hyaluronidase, the PS is released and its photo-mediated activity is restored, leading to a localized photodynamic effect. Following a single laser irradiation at 607 nm, the nanosystem exhibited a synergistic PTT/PDT anti-tumoral activity and showed promising results in vitro and in vivo. which offers an efficient PS delivery in the targeted site. Undesired pre-leakage of the PS from PDA surface could however be observed limiting consequently the therapeutic efficiency and increasing the side effects. Improved stability may hence be achieved through covalent coupling of the PS to the nanostructure.

PS covalently bound to the surface of PDA nanomaterials

Zhang et al. reported the preparation of Ce6-carrying PDA nanospheres via covalent binding between the carboxylic acid of the PS and the amine groups exposed on polydopamine surface, using carbodiimide chemistry [193]. The combined photothermal and ROS-mediated effects, associated to PDA and Ce6 respectively, resulted in a significantly enhanced anticancer therapeutic efficacy as demonstrated through vitro and in vivo studies, following a dual-wavelength laser irradiation (808 nm for PDA activation and 670 nm for Ce6) [193].

This carbodiimide-mediated conjugation strategy has been later employed by Wang et al. for the immobilization of the PS Ce6 on the surface of PDA nanoparticles. However, in order to improve the selectivity and therapeutic efficacy of this nanomedicine, the authors decorated herein the Ce6-bearing PDA nanospheres with a tumor targeting moiety, hyaluronic acid (HA), which offered a remarkably higher tumor penetration and resulted in a superior synergistic anti-tumor effect in comparison to the non-targeting platform [254] .

In an another approach, Yang et al. [258] selected black phosphorus (BP) nanosheets (NSs), biocompatible and biodegradable inorganic materials, as the nanocarrier for Ce6 delivery, taking advantage of its high surface area that offers considerably high loading amounts of the PS. PDA was used here to coat the NSs and served as a bridge to enable the covalent anchoring of Ce6 and triphenyl phosphonium (TPP), a mitochondria-targeting moiety, using carbodiimide chemistry for both reactions. Under a single 660 nm irradiation, the combination of PDA and BP in the nanosystem resulted in an increased photothermal conversion efficiency, with 33.2 % for PDA@BP NSs versus 26.6 % for BP NSs alone, while Ce6 In order to achieve a superior treatment efficacy and ensure its biosafety, it is highly desirable to design smart nanocarriers that specifically deliver the PS to the targeted tumor tissue and in a controlled manner. In this context, a smart PDT/PTT controllable platform was proposed by Although the excellent activity of these systems has been largely demonstrated through in vitro and in vivo models, the direct immobilization of the PS on polydopamine results in a partial decrease in the PS-mediated ROS generation [250,258], due to the redox activity of PDA and its ROS scavenging capacity. This issue should be considered by coupling the PS to PDA nanoplatforms through hydrophilic polymers, such as polyethylene glycol. ZnP: Zinc Porphyrin, JNPs: Janus nanoparticles, NCs: nanocapsules, PNAm; Poly(N-acryloyl glycinamide-co-acrylamide), TPGS: D-α-tocopheryl poly(ethylene glycol) 1000 succinate

Multi-modal cancer therapy

In order to reach better therapeutic outcomes, multi-modal cancer therapy is widely adopted for cancer treatment. Diverse all-in-one innovative PDA-based platforms have been described

in the literature as multifunctional/multi-modal therapeutic or theranostic nanoagents [159] [264, 267]. Numerous reviews published over the recent years have cited in great details the diverse therapeutic approaches and associations described regarding PDA-mediated anticancer treatment [29-32, 165, 268].

Other catecholamines-derived melanin-like materials

The outstanding properties of PDA-based materials and their remarkable potential in diverse biomedical applications, particularly in the cancer therapy field, have boosted the research of new melanin-like materials for the design of novel therapeutic agents. Catecholamines like 3,4-dihydroxy-L-phenylalanine (L-DOPA) or norepinephrine, and other related molecules like serotonin, have been considered for the development of bio-inspired advanced functional materials. Other naturally occurring catechols or dopamine chemical derivatives [START_REF] Ryu | Polydopamine Surface Chemistry: A Decade of Discovery[END_REF][START_REF] Lee | Material-Independent Surface Chemistry beyond Polydopamine Coating[END_REF]166] were also described in the literature for the preparation of polydopamine-resembling materials. Natural melanin granules have also gained interest as photothermal and photoacoustic agents showing high photothermal conversion efficiency (about 40 %) and excellent activity revealed through in vitro and in vivo assays [269-271] .

The small structural differences between precursor monomers may result in a divergence in the functional properties and biological performance of the corresponding polymerized structures, which would offer a rich repertoire of melanin-mimicking materials of tailored characteristics.

Here, we will describe the ability of three main precursors, namely L-DOPA, norepinephrine and serotonin, to give rise to polydopamine-like "polymers" following their oxidation In comparison to PDA nanoparticles, PDOPA counterparts displayed a stronger NIR light absorption and exhibited an enhanced photothermal conversion efficiency under laser illumination at 808 nm and a power density of 2 W.cm -2 [273]. These properties can be advanced to develop photothermal therapeutic nanoagents with a great potential in cancer treatment applications.

6.2.Poly(norepinephrine), PNE

Norepinephrine is another endogenous catecholamine that, similarly to the parent dopamine and L-DOPA, can spontaneously polymerize under ambient alkaline conditions. The synthesis of poly(norepinephrine) (PNE) was first reported in 2009 after polydopamine discovery [282].

PNE was at first mostly reported as a versatile coating material applied to coat substrates of different types and shapes including nanoparticles [283], nanotubes [284] and nanofibers [285] and could deposit on the surface of several organic and inorganic substrates including polymers, metals, silicates and graphene oxides [286-287] .

Following the protocols described for polydopamine formulation, spherical monodisperse Owing to its bio-inspired nature and this highly hydrophilic character, PNE nanoparticles exhibited excellent biocompatibility as demonstrated in in vitro and in vivo studies and showed no immune response or long-term toxic effects during in vivo studies [288][289][294][295].

Considering all these aspects, PNE nanomaterials have gained increasing attention for biomedical applications, including tissue engineering [296] and gene delivery [297] applications, and have recently emerged as smart thermal and/or pH responsive drug delivery platforms and excellent photothermal nano-agents, applied for combined chemo-PTT cancer therapy.

Indeed, due to its composition rich in aromatic rings, PNE nanoparticles are able to load compounds with aromatic rings, like doxorubicin, and hold a great potential as anti-cancer drugs nanocarriers [288,298]. Interestingly, PNE nanoparticles showed excellent drug loading ability with a maximum loading capacity of DOX that exceeded greatly that of PDA counterparts. Besides, PNE nanoparticles exhibited a higher cellular uptake efficiency, which resulted in a significantly enhanced intracellular DOX accumulation in comparison to polydopamine, confirming hence their superior potential in drug delivery applications. Similar to polydopamine, PNE nanomaterials showed a pH-sensitivity leading to a reduced leakage during blood circulation and to an enhanced drug release in acidic tumor microenvironment and cytolysosome compartments, due to the protonation of the amine functions in PNE causing the disruption of the- interactions.

Moreover, very recently, PNE nanomaterials were revealed to be a promising photothermal converting nanoagent of a great potential in cancer therapy. Indeed, PNE nanoparticles displayed a high NIR light absorption and an excellent photothermal conversion efficiency of 67% for nanoparticles of ~ 100 nm, following their irradiation at 808 nm, which is a 1.63-fold higher than that of their PDA analogues (41%), and higher than most available PTT

Poly(serotonin), PST

Poly(serotonin) (PST) is a less explored class of melanin-like material obtained from the oxidative self-polymerization of serotonin, an indoleamine neurotransmitter derived from the hydroxylation and decarboxylation of the amino acid tryptophan.

The polymerization process, conducted under alkaline conditions, generated monodisperse nanoparticles, whose formation occurred with significantly slower kinetics compared to polydopamine, as monitored using absorption spectroscopy [299].

The drug loading ability, stimuli-responsiveness and photothermal activity of PST nanoparticles have been recently investigated. The anticancer drug DOX was tested and could be efficiently loaded on the surface of PST nanoparticles via - and hydrophobic interactions and through hydrogen bonds formation. However, the drug loading efficiency was found to be lower than that of PDA nanoparticles. A controlled pH-induced release of the chemotherapeutic drug was depicted, confirming the interest of PST-based nanosystems in drug delivery applications for tumor therapy.

Moreover, the illumination of PST nanoparticles suspensions at 808 nm and 1.5 W.cm -2 induced a solution temperature increase of > 20 °C for nanoparticles concentrations > 100 µg.ml -1 . The temperature increase generated by PST nanoparticles was however lower than that obtained for their PDA counterparts.

Nevertheless, although the photothermal activity and drug loading capability of PST nanoparticles were limited compared to polydopamine materials, the former represent promising anticancer nanoagent candidates. Particularly, PST nanoparticles showed a greater biocompatibility, and a reduced protein corona formation in comparison to polydopamine, which is highly interesting for in vivo applications. Indeed, at the nano-bio-interface polyserotonin nanoparticles showed reduced interactions with proteins corona as suggested by quantum mechanics computations, which was attributed to the four-folds lower adhesion obtained for PST nanoparticles compared to PDA during peak-force AFM experiments.

Based on these findings, PST-based nanoparticles can be used as a multifunctional cancer therapeutic nanoagent working as a photothermal agent and a drug nanocarrier for efficient anticancer therapy with a minimal toxicity.

Summary and outlooks

In summary, polydopamine represents a successful example of nature-inspired materials.

Considering its diverse inherent properties, including the excellent biocompatibility, the high chemical reactivity and the remarkable photothermal conversion ability, PDA is acknowledged as a robust element that can be considered for the development of innovative "all in one" platforms, in order to provide an efficient cancer treatment and diagnosis.

Nevertheless, despite the rapidly increasing implementation of polydopamine and catecholamines derivatives in nanomedicines research field, several remaining challenges still have to be overcome to achieve advancements towards future clinical translation.



Regarding the complicated formation mechanisms, thorough investigation based on advanced techniques should be undertaken for a better understanding of the molecular organization and assembly modes. This would offer a full control of the morphological and functional features of polydopamine materials, allowing consequently the expansion of their applications scope.



The purification methods described so far to separate PDA nanoparticles from the oligomeric and unpolymerized counterparts are mostly based on dialysis or centrifugal filtration. However, these latter seem to be inefficient to separate all of the oligomeric structures from PDA nanoparticles and especially when it comes to nanoparticles with a hydrodynamic diameter less than 100 nm. The presence of such oligomeric structures in PDA nanoparticles suspension would affect their physicochemical properties and their in vivo outcomes.



As the preparation method leads to different chemical structures of PDA assemblies, this may affect their physicochemical properties and thus their interaction with biological environment. Hence, the preparation procedures should be harmonized between the different studies in order to get a relevant comparative set of data regarding the in vitro or in vivo studies.



Full comprehensive studies of the photothermal conversion efficiencies of polydopamine nanostructures as a function of particles size and preparation procedures are also still lacking.



Moreover, due to the high chemical reactivity and sensitivity of polydopamine structures, precautions need to be taken during formulation, use and storage, in order to avoid undesired side reactions.



As for the biosafety of such materials in humans, the biocompatibility of polydopamine was established based on observations made on cells and animal models (mice or rats). A better understanding of the pharmacokinetics profiles, the behavior towards physiological barriers, and the biodegradation pathways needs to be fulfilled.

Figure 1 .

 1 Figure 1. Polydopamine, a nature-inspired polymer, (A) The molecular composition of Mytilus edulis foot proteins rich in DOPA and lysine amino acids inspired the preparation of a strongly adhesive coating material, polydopamine, obtained from dopamine oxidation, (B) The oxidative polymerization of dopamine leads to a eumelanin-mimicking structure.

Figure 2 .

 2 Figure 2. Applications of polydopamine nanomaterials in cancer therapeutic / theranostic fields.

Figure 3 .

 3 Figure 3. Illustration of the preparation methods used for polydopamine synthesis: (A) Solution oxidation of dopamine and typical parameters and additives controlling dopamine oxidation and polymerization rates, and the structural characteristics of nanoparticles size and coatings deposition, (B) Enzyme-catalyzed oxidation of dopamine following a melanin biosynthesis-mimicking approach, (C) Anodic oxidation of dopamine. FA: Folic acid, TMB:1,3,5-trimethylbenzene

Figure 4 .

 4 Figure 4. Nanomechanical study performed on PDA nanoparticles, (A-D) AFM height images in Tris buffer of covalently attached PDA NPs with different sizes on silanized mica substrates with their corresponding Young's modulus maps (E-H) obtained with JPK Quantitative imaging (QI) mode at a force setpoint of 35 nN and an indentation speed of 50 µm s -1 , (I-L) represent the histograms distribution of the Young's modulus of NPs with Gaussian fits [54].

Figure 5 .

 5 Figure 5. Most common interactions (covalent, non-covalent and coordination) involved in polydopamine functionalization.

For

  eumelanin, contrary to what has been though at first, the broad-band absorption does not originate from scattering phenomena[203] but corresponds effectively to an intrinsic light absorption. Indeed, based on accurate measurements of the optical scattering coefficient, it was found that the contribution of Rayleigh scattering is lower than 6 % of the total optical attenuation in the 210 to 325 nm region and is undetectable for the wavelengths ranging between 325 and 800 nm[201]. Similarly, Warren et al. confirmed recently that, for polydopamine also, the optical spectrum reflects real absorption and is not significantly altered by scattering effects[134].

  ].Chen et al. showed that the excitonic effects of the eumelanin aggregated stacked oligomers (protomolecules) has a great role in the broad-band absorption. The protomolecules being in different sizes and randomly oriented, the interplay of the geometric order / disorder in the aggregated eumelanin structures would result in random and significant excitonic couplings through the formation of electron-photon pairs, leading to the broadening of the absorption chromophore band along with the enhancement of the absorption towards higher energies[207]. The contribution of aggregation and structural scaffold disorder, as well as the redox dynamics, in the eumelanin chromophore broad band were also investigated and confirmed byMicillo et al. [208].

Figure 6 .

 6 Figure 6. Simplified scheme of chemical disorder levels in eumelanins realized through structural definitions at multiple length-scales in the hierarchy of the material (adapted from [127])

Figure 7 .

 7 Figure 7. Structure-property relationship proposed by Warren's group for melanin-like materials including polydopamine, based on the geometric disorder model. The hierarchical assembly would play a role to extend the broad absorption band to low energies (adapted with permission from [134]).

[

  216], into four strategies consisting in polydopamine (i) chemical oxidation[217], (ii) degradation[218], (iii) conjugation[192] or (iv) carbonization[219]. These strategies were mainly based on the reduction/weakening of the - interactions present in polydopamine scaffold or on the reduction of dopamine polymerization degree, hindering hence the aggregation-caused quenching effect, or also on the creation of distinct sp 2 and sp 3 hybridized carbon atoms, introducing thus the fluorescence properties.For instance, the oxidation of polydopamine particles using hydrogen peroxide has emerged as a facile novel method allowing the synthesis of fluorescent organic nanoparticles with a tunable fluorescence emission[220][221][222]. Interestingly, the obtained PDA nanoparticles displayed two-photon fluorescence properties under NIR light excitation, which permits to reach a superior penetration depth during tissue bio-imaging. The same route was also reported for the preparation of fluorescent PDA shells and the development of fluorescent PDA nanocapsules[START_REF] Liu | Recent developments in polydopamine: an emerging soft matter for surface modification and biomedical applications[END_REF]. Besides, based on the high ROS rates, and particularly H 2 O 2 , in the tumor microenvironment in comparison to normal tissues, PDA oxidation-mediated fluorescence generation can be explored for tumor diagnosis / operation applications[221].

Figure 8 .

 8 Figure 8. ICG-loaded polydopamine-reduced graphene oxide (rGO) nanocomposites with amplified photothermal and photoacoustic effects for cancer theranostics, (A) Schematic illustration of the preparation process of ICG-PDA-rGO, (B) Photothermal heating curves of PBS, GO, PDA-rGO and ICG-PDA-rGO solutions, CGO=CPDA-rGO=CICG-PDA-rGO=20 mg.l -1 , (C) Photothermal heating curves of ICG-PDA-rGO solutions of different concentrations , (D) Temperature evaluation of ICG-PDA-rGO and equal free ICG solutions over four laser ON/OFF cycles. (laser ON time: 5 min, laser OFF time: 5 min), (E) UV-vis absorption spectra of free ICG and ICG-PDA-rGO solutions before and after four cycles of laser irradiation at 808 nm and 0.6 W.cm -2 . (Printed with permission from[235] ).

(

  type II PDT reactions) [233]. Although highly promising, PSs usually suffer from poor water solubility limiting their bioavailability and therapeutic efficacy, which renders interesting their encapsulation and administration using nanocarriers. These latter allow to considerably improve the biodistribution of photosensitizers and enhance their membrane permeability, resulting in enhanced therapeutic efficacy and minimal side effects. In this context, PDAbased nanostructures have emerged as promising nanocarriers for photosensitizing agents and have thus been largely applied in anti-cancer PDT. For example, taking advantage of the negative charge of polydopamine, Yan et al. synthesized a highly positively charged zincphthalocyanine, the ZnPc(TAP) 4 12+ , which allowed the physical adsorption, of this watersoluble phthalocyanine derivative, on the surface of PDA nanoparticles via electrostatic interactions. The nanosystem was further modified with a tumor targeting moiety, folic acid (FA), which offered a high tumor accumulation and resulted in specific and efficient cancer cells eradication [186]. A resembling system was previously proposed by the same group of researchers in which both ZnPc(TAP) 4 12+ and nocodazole (NOC), a cell cycle inhibitor, were immobilized on PDA nanoparticles surface using electrostatic interactions for an enhanced synergistic anti-cancer therapy [252]. Another promising nanomedicine was proposed by Liu et al. who developed an innovative oxygen-self supplied platform composed of a photosensitizer, methylene blue, carried by polydopamine-hemoglobin complexes encapsulated inside a bio-vesicle engineered from recombined red blood cells (RBCs) membranes and serving as oxygen carrier and supplier

5. 2 .

 2 photosensitizing agent or generated singlet oxygen[250]. On the other hand, the oxygen depletion taking place in the tumor microenvironment during PDT renders the cells more sensitive to heat, enhancing thereby the efficacy ofPTT [254].

Figure 9 .

 9 Figure 9. (A) PDA/PS nanoplatforms for synergistic photothermal/photodynamic therapy, (B) Strategies of PS coupling to PDA nanostructures.

5. 2 . 3 . 2 .

 232 PS adsorbed onto the surface of PDA nanomaterials Diverse physical interactions could be deployed for the loading of PS on polydopamine, particularly via - interactions, hydrophobic interactions, hydrogen bonding or electrostatic interactions. Multiple PS-bearing polydopamine nanosystems have been described for this category. Wang et al. proposed a multifunctional drug delivery platform, based on PDA-coated gold nanorods (GNRs), for multi-modal cancer theranostics [155]. The nanohybrid was further functionalized with PEG which increased its colloidal stability and a photosensitizer, methylene blue (MB), was then adsorbed on the surface of polydopamine via electrostatic and - interactions. The association of GNRs to PDA resulted in an improved PTT performance which allowed an efficient tumor ablation, as demonstrated in vitro and in vivo. The combination of hyperthermia and ROS generation associated to MB, promoted the anti-cancer therapeutic efficacy.

  In a more recent study, Chen et al. proposed a novel PDA-based PDT-PTT dual platform in which aggregation-induced emission (AIE) gens were used as efficient photosensitizing agents[257]. Herein, a mitochondria-targeting AIE PS conjugate was attached to the surface of polydopamine nanoparticles via - interactions, H-bonding and electrostatic attraction, and showed an unprecedently high loading capacity with a low leakage rate. A synergistic PDT/PTT-mediated tumor inhibition was indeed obtained in vitro and in vivo and was associated to a low IC 50 of 71 µg.ml -1 versus 170 µg.ml -1 or 105 µg.ml -1 for PDT (white light, 100 mW.cm -2 ) or PTT (808 nm laser, 1 W.cm -2 ) alone, respectively. The nanohybrid system displayed a positive surface charge which resulted in pronounced cytotoxic effects.The physical adsorption of the photosensitizing molecules on the surface of PDA nanoparticles or shells uses relatively simple chemical procedures for molecules immobilization, in comparison to covalent conjugation. Although such interactions are energetically weak, studies have demonstrated their relative stability under physiological conditions. They are on the other hand easily weakened under the acidic, reductive or oxidative conditions characterizing the tumor microenvironment or under NIR irradiation,

  phototherapeutic efficiency, as demonstrated in in vitro and in vivo cancer models. Other covalent interactions were engaged for the design of similar bimodal photoactivatable nanoagents. For instance, Hu et al. have developed C 60 -PDA-graphene nanohybrids as a promising anti-cancer candidate for synergistic PT/PD therapies [250]. In this study, fullerene C 60 , a promising photodynamic agent, was conjugated to the targeting moiety folic acid (FA), and the resulting conjugate was anchored on PDA-rGO nanohybrid using nucleophilic Michael addition or Schiff base reaction of the amine-terminated FA on the o-quinone function of polydopamine. The covalent attachment of C 60 -FA conjugate on the nanohybrid

  photodynamic/photothermal effects allowed the efficient cancer ablation.The covalent conjugation of the PS offers a higher stability and biosafety to the nanomedicine and allows an efficient delivery of the molecule to the targeted site. The design of smart stimuli-responsive delivery systems allows to further control the release behavior of the PS for a higher efficiency. Nonetheless, more efforts are still needed for the development of such systems, through exploring the potential of diverse smart cleavable linkers, which would offer a spatio-temporally controlled release under external stimuli.

Scheme 3 .

 3 Scheme 3. Structures of the main monomers explored for the synthesis of polydopamine-resembling materials

  PNE nanoparticles were successfully prepared, using a NaOH solution[288] or an alkaline Tris buffer / ethanol mixture[289]. Their size and morphology were tunable by varying the monomer or solvent amounts. For instance, increasing the monomer amount led to the increase of nanoparticles size. The increase of ethanol concentration allowed the obtention of nanoparticles of smaller size, while the use of ethanol at very low concentrations (0.1 mM) induced a loss in their spherical shape and monodispersity, which was attributed to the Hansen solubility parameter theory, as for polydopamine formation.Similar to polydopamine, PNE materials expose multiple reactive sites serving as anchors for the immobilization of diverse biomolecules (enzymes[284,[290][291], antibodies [292], etc.) and for nanoparticles functionalization using PEG chains[288].In comparison to its polydopamine analogue, conventional PNE present an ultra-smooth and a highly homogenous surface, due to the presence of 3,4-dihydroxybenzaldehyde, an intermediate generated during the polymerization of norepinephrine[293]. This property is advantageous for biomedical applications and allows to overcome limited surface regularity encountered in polydopamine[286]. Indeed, PNE nanoparticles showed increased hydrophilicity and enhanced anti-fouling properties in comparison to their PDA counterparts suggesting a superior potential in biological applications[289] and PNE coatings served as an interesting bio-interface used to endow coated biomaterials with high hydrophilic and antifouling properties[289]. Moreover, following the immobilization of an enzyme on the PDA or PNE surfaces, higher enzyme loading rates were obtained for PDA due to this latter's rougher surface, however a decreased enzyme activity was observed and attributed to a reduced accessibility of its active sites[284]. The higher hydrophilicity of PNE counterparts allowed on the other hand to promote the activity of the immobilized enzyme.

  photothermal effect for an efficient tumor ablation.Similarly, PNE coatings have shown promising photothermal activity and drug loading ability and were explored for the development of novel artemisinin-loaded PNE-coated FeOOH nanoparticles for efficient cancer photothermal-chemical combination therapy[298].

Preparation method Obtained nanostructures Impact on nanostructures properties Ref

	Basic buffers (Tris, Phosphate,	Preparation of PDA-coated structures,
	Bicarbonate),	Few nm to few hundreds of nm
	in presence of substrates

Table 2 .

 2 Examples of nanosystems types modified by polydopamine and the role PDA shell in the proposed system

	Coated core		Preparation method of PDA	Properties / Functionality of PDA layer	Application	Ref
			layer
	Inorganic	Gold	Tris buffer (10 mM, pH 8.5),	Thickness = 30 nm.	PDT-PTT	[155]
	cores	nanostructures, like	[DA] = 1 mg.ml -1 ,	Photothermal effects,
		gold nanorods	Vortex and sonication for 35 min	Drug carrier for PDT (methylene blue) or CT (Doxorubicin).
		Au-Ag branched	Tris buffer (10 mM, pH 8.5),	Thickness = 6-34 nm.	Synergistic PTT	[156]
		NPs	[DA] = 0.04-0.22 mg.ml -1 ,	Photothermal effects,
			3 h	Prevention of the release of toxic metals from the NPs core,
				Enhancement of NPs biocompatibility,
				Preservation of the branched structure of the NPs.
		Fe 3 O 4 NPs	[DA] = 0.12 mg.ml -1 , PBS buffer (10 mM, pH 8.5),	Photothermal effects, Thickness = 4 nm.	imaging-guided PTT MRI and PA	[157]
			Shaking for 4 h	Adsorption of dye-labeled single-stranded DNA (ssDNA), for the
				detection of mRNA for cancer diagnosis,
				Fluorescence quenching of the probe, hindering its off-target
				activation.
		(Mesoporous NPs) MnO 2 NPs	[DA] = 1 mg.ml -1 , Tris buffer (10 mM, pH 8.5),	drug release in the tumor acidic microenvironment, Prevention of drug pre-leakage during circulation, pH-responsive	PDT-PTT	[158]
			6 h	Anchoring of NH 2 -PEG-FA (for anti-fouling properties and active
				targeting of tumor).
		CaCO 3 NPs	NH 4 HCO 3 decomposed into CO 2	Thickness = 44 nm.
			and NH 3 gas, ethanol, solution of Ca 2+ and dopamine,	Preparation of hollow PDA-CaCO 3 nanoparticles, Immobilization of a lipid bilayer of DOPA, DPPC, cholesterol and
			Dopamine/CaCl 2 = 2/150 (m/m),	DSPE-PEG,
			24 h	Loading of the PS Ce6 and prevention of its photobleaching,
				pH-responsive drug release in the tumor acidic microenvironment,

Table 3 .

 3 Examples of Michael addition and/or Schiff base condensation reactions explored for the development of PDA-based nanosystems

	Grafted molecule	PDA-based system	Reaction conditions	Applications	Ref
	Thiolated poly(methacrylic acid)	PDA NCs	pH 8.0	Immobilization of DOX,	[179]
	(SH-PMA) -pH cleavable		Overnight incubation	Preparation of a stimuli-responsive DDS for an
	hydrazine bond -Doxorubicin		In presence of TCEP (to prevent	intracellular delivery of the anti-cancer drug
	(DOX)		the oxidation of thiol groups)
	Thiol-or amine-terminated	PDA NPs	≥ pH 8.0	Improvement of PDA NPs colloidal stability for in vivo	[184,
	poly(ethylene glycol)		Overnight incubations	applications	189]
	Thiol-terminated hydroxyethyl	PDA NPs	pH 10.0	Improvement of the PDA NPs colloidal stability for in	[180]
	starch (HES)		24 h incubation	vivo applications, using a coating with a favorable
				biocompatibility and biodegradability (superior to PEG-
				modified PDA NPs)
	SH-PEG -folic acid (FA)	PDA-modified	pH 8.5	Grafting of a cancer targeting moiety for enhanced anti-	[190]
		mesoporous silica NPs	In presence of TCEP (to prevent	tumor therapy efficiency
			the oxidation of thiol groups)
	Folic acid (FA)	PDA-coated Au-Zein	pH 8.5	Grafting of a cancer targeting moiety for enhanced anti-	[183]
		nanocomplexes	1 h incubation	tumor therapy efficiency
	Galactosamine (amin-bearing	PDA NPs	pH 8.5	Grafting of a tumor targeting moiety for specific liver	[187]
	tumor targeting moiety)		2 h incubation	tumor targeting

Table 4 .

 4 Examples of PDA-based nanoplatforms used for mono-or multi-modal cancer therapy

	Nanosystem	Targeting moiety	Cargo	Applications	Properties	Testing stages	Ref
	configuration
	PDA NPs	Ovalbumin (tumor	--	Immunotherapy	vaccine delivery	in vitro: C57BL/6 (murine	[181]
		model antigen)				colon cancer)
						in vivo: colon-cancer model
	Fe 3 O 4 -PDA NPs	Bortezomib (BTZ)	--	CT,	pH-responsive drug release:	--	[242]
				MRI guidance	-at pH 7.4: 1.7 μM in 10 h
					-at pH 5.5: 4.7 μM in 10 h
					-at pH 4.0: 5.0 μM in 10 h
	Magnetic Nanocrystal	Cisplatin	--	CT,	pH-responsive drug release:	in vitro: HeLa cells (human	[240]
	Clusters (MNCs) @ PDA shell			Magnetic guidance	-at pH 7.0: 38% in 24 h -at pH 5.0: abrupt release	cervical cancer), MCF-7 cells (human breast adenocarcinoma)
	Mn / SS /PEG-PDA NPs	Doxorubicin (DOX)	--	CT	pH and redox-responsive DOX release	in vitro: 4T1 cells (breast	[243]
				MRI guidance	-at pH 7.4: 20% in 24 h -at pH 5. : 40% in 24 h -at pH 7.4 + GSH: 45% in 24 h	cancer), HeLa cells, K7M2 (murine osteosarcoma)
					-at pH 5.5 + GSH: 70% in 24 h	in vivo: 4T1-bearing tumor
						mice (breast cancer model)
	PDA-modified MSNs	DOX	Folic acid	Targeted CT	pH-responsive DOX release:	in vitro: HeLa cells	[190]
			(FA)		-at pH 7.4: 28.5% in 190 h -at pH 5.6: 38.3% in 190 h -at pH 2.0: 49.5% in 190 h	in vivo: HeLa-bearing tumor mice (cervical cancer model)

Table 5 .

 5 PDA-based nanoplatforms applied in light-mediated cancer therapy, PDT and/or PTT

	Nanosystem	Targeting	Loaded PS Properties	Applications Illumination conditions	Testing stages	Ref
	configuration	moiety
	Ce6-PDA NPs	--	Ce6	High loading amounts of Ce6	PTT-PDT	PTT/PDT: 665 nm, 250 mW.cm -2 , 15	in vitro: T24 cells	[199]
						min	(bladder cancer)
	Ce6-PDA NPs	--	Ce6	Increased photostability	PTT-PDT	PTT: 808 nm, 2 W.cm -2 , 5 min for in	in vitro: HepG2 cells	[193]
						vitro and 10 min for in vivo tests;	(liver cancer)
						PDT: 670 nm, 50 mW.cm -2 , 5 min for in vitro and 10 min for in vivo	in vivo: HepG2 -bearing mice
						tests
	Ce6-PDA NPs	Hyaluronic	Ce6	Enhanced cellular internalization	PTT-PDT	PTT: 808 nm, 2.5 W.cm -2 , 5 min for	in vitro: HCT-116	[254]
		acid (HA)		(CD44-mediated endocytosis)		in vitro and 10 min for in vivo tests;	cells and 3D tumor
							spheroids (colorectal
						PDT: 670 nm, 50 mW.cm -2 , 5 min	cancer)
						(for in vitro tests) or 10 min (for in vivo tests)	in vivo: HCT116 -bearing mice
	PDA-Ce6-GSH-Au nanoflowers (NFs)	--	to the Au via GSH) (conjugated Ce6	of AuNFs, Lower dark toxicity photothermal conversion efficiency ~80 nm and amplified the Induced a significant red shift of	PDT PTT effects -Synergistic	(for in vitro tests) or 10 min (for in PDT: 660 nm, 100 mW.cm -2 , 5 min in vitro and in vivo tests); PTT: 808 nm, 2 W.cm -2 , 10 min (for	bearing mice in vivo: HeLa -(cervical cancer) in vitro: HeLa cells	[260]
						vivo tests)