Advanced metal-phenolic networks for tissue regeneration: opportunities and challenges

Abstract

Owing to their commendable biocompatibility, unique physicochemical properties, and highly tunable structural characteristics, metal polyphenolic networks (MPNs) have emerged as a highly promising class of functional materials, exhibiting broad application prospects in the field of tissue regeneration. This study provides a comprehensive review of the effects of MPNs and their composites on cells and tissue regeneration. It meticulously highlights the mechanisms of action of MPNs and their primary synthesis methods. Furthermore, the properties of MPNs that facilitate tissue regeneration are discussed, along with their promotive effects on the repair of various tissues, including skin wounds, bone/cartilage, joints, the heart, nerves, and teeth. Finally, the challenges faced by MPNs are outlined, and future perspectives in this field are presented, aiming to provide new opportunities and pathways for the application of MPNs-based materials in tissue regeneration.

Graphical Abstract

Introduction

The key challenge in complex tissue regeneration does not lie in simply filling tissue defects, but in how to construct functional biomaterials that can adapt to the damaged microenvironment and coordinate the multi-stage repair process [1–4]. The ideal regenerative material should not only have good biocompatibility, structural adaptability and processability, but also be capable of dynamically responding to key pathological processes such as inflammation, oxidative stress, infection and vascular reconstruction, thereby achieving precise regulation of the tissue repair process [5–7]. However, many tissue engineering materials remain constrained by insufficient functional integration, limited microenvironment regulation ability, and weak adaptability for clinical transformation, making it difficult to meet the actual needs of complex tissue regeneration [8–10]. In recent years, metal polyphenolic networks (MPNs) have gradually become highly promising material platforms in regenerative medicine due to their advantages such as mild assembly conditions, component adjustability, interface universality and synergistic multifunctionality [11].

Inspired by the natural mussel adhesion mechanism and the chemical properties of plant polyphenols, polyphenols with catechol or pyrogallol groups, exhibit excellent metal ion coordination ability, interfacial adhesion performance, and antioxidant activity, thus becoming an important molecular foundation for constructing high-performance biomaterials [12, 13]. Based on this, MPNs, can be rapidly constructed under mild conditions and further processed into nanoparticles, surface coatings, hydrogels, and other composite structures. Compared with polyphenol self-assembly systems without metal participation, MPNs fully leverage the synergistic effects between metal ions and polyphenol molecules, resulting not only in significantly enhanced structural stability but also in diversified functional expansion [14]. By rationally selecting metal types and polyphenolic ligands, MPNs can not only exert the antioxidant, anti-inflammatory, and interfacial regulation effects of polyphenols but also introduce the biological effects of metal ions such as antibacterial, pro-angiogenic, osteogenic, or immunomodulatory properties [15–17]. For instance, copper-based MPNs have been used for antibacterial and pro-angiogenic repair of infected wounds, while magnesium- or strontium-containing MPN systems have shown promising immunomodulatory and tissue regenerative capabilities in bone and cartilage regeneration [18–20]. Additionally, the dynamic coordination characteristics of MPNs endow them with responsiveness to external and internal stimuli such as pH, ROS, and near-infrared light, enabling controlled release of drugs or bioactive components, thereby better accommodating the on-demand therapeutic requirements of complex injury microenvironments [21, 22]. Given the aforementioned advantages, MPNs have been regarded as a highly promising functional material in the field of tissue regeneration, and they have demonstrated significant application potential in repair models for various tissues, including skin, bone, cartilage, nerve, cardiac, and, arthrosis.

This review aims to systematically summarize the latest research advancement on MPNs in various tissue regeneration (Fig. 1). It establishes a foundation by elucidating their chemical composition, formation mechanisms, and core physicochemical properties. Subsequently, it focuses on critiquing the specific application strategies and mechanisms of action of MPNs in various tissue repair and regeneration, including their regulatory effects on cellular behaviors and the immune microenvironment, as well as the mechanisms for enhancing regenerative outcomes. Finally, by considering current research bottlenecks and development trends, the review provides an outlook on future design strategies for MPNs-based materials and their clinical translation pathways, intending to offer theoretical reference and practical guidance for developing the next generation of regenerative medicine materials.

Fig. 1.

Schemic diagram of MPNs for tissue repair and regeneration

Composition and structure of MPNs

Polyphenols

Polyphenols are organic molecules containing phenolic hydroxyl groups that are widely found in the bark, roots, leaves, and fruits of plants. Due to their excellent free radical scavenging, anti-inflammatory, antibacterial and immunomodulatory effects, polyphenols have been widely used to treat a variety of diseases, including diabetes, cerebrovascular diseases, obesity, cancer, and tissue repair [23–25]. There are two main groups of polyphenols: flavonoids and nonflavonoids [26]. Polyphenols include a variety of molecules, such as catechins, tannins, curcumin, EGCG, resveratrol, etc. Figure 2 shows the structural formula of common polyphenols.

Fig. 2.

The structure of classic polyphenols

Flavonoids

The basic skeleton of the flavonoid is C6-C3-C6, which consists of two phenolic units linked by a pyranoheterocycle [27]. Based on variations in the hydroxylation pattern and the degree of oxidation of the heterocyclic pyran ring, flavonoid compounds can be further divided into different subgroups of flavanols, flavones, flavanols, isoflavanones, and anthocyanin. The chemical properties and bioavailability of flavonoids are related to the specific substitution of chemical groups in their core structure [28]. Tea polyphenols, which comprise flavonoids, flavanols, phenolic acids, and anthocyanins, represent the principal group of polyphenolic compounds in green tea and are associated with numerous beneficial biological activities [29]. The most abundant and biologically active constituents among these are catechins, such as (−)-epicatechin (EC), (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epigallocatechin-3-gallate (EGCG) [30]. Among them, EGCG exhibits the highest content and the most potent biological activity.

Non-flavonoids

Generally, non-flavonoid polyphenols include phenolic acids, stilbene, and lignins. Phenolic acids have a carboxyl group attached to the benzene ring and include cinnamic and benzoic acids [27]. Hydroxycinnamic acid is found mainly in fruits, vegetables, tea, and coffee, examples of major derivatives are ferulic acid, caffeic acid, octanoic acid, and coumaric acid [31]. Hydroxycinnamate esters exist as monomers, dimers, and combinations of esters or amides. For example, chlorogenic acid, which is the condensation of one or more trans cinnamic acids and quinine or their derivatives, is mainly present in coffee beans and has attracted wide attention due to its potential biological effects such as anti-inflammatory, antibacterial, anti-cancer and anti-diabetic activities [32]. Examples of benzoic acid derivatives are gallic acid, syringic acid, vanillic acid and p-hydroxybenzoic acid. Gallic acid can be extracted from natural plants and is widely used in medical and food fields. It can inhibit the growth and biofilm formation of Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, and shows a broad spectrum of antibacterial effects [33].

Stilbenoids are non-nitrogen polyphenols, acidic and amphiphilic, composed of ethylene Bridges connecting two aromatic rings in cis and trans forms, with the trans form considered to be the primary biological structure of stilbenoids [12]. Stilbenoid compounds are widely found in bryophytes, gymnosperms, ferns, and magnolia plants. The common stilbene compounds mainly include the common natural stilbene compounds including resveratrol, oxidized resveratrol, picrotaxol and pterostilbene.

Lignans are a class of naturally occurring compounds that are non-flavonoid polyphenolic compounds resulting from oxidative dimerization of two phenylpropane units; the monomers forming lignans are cinnamyl alcohol, cinnamic acid, allyl benzene, and allyl benzene [34]. Lignans are widely found in plants, with flaxseed being the richest plant source of lignans. Lignans have been shown to have free radical scavenging, antioxidant, anticancer and antidiabetic and gene expression regulating effects in the body. Due to its low toxicity, few side effects and good degradation properties, lignans not only serve as delivery vehicles in drug delivery systems, but also can be used as therapeutic agents [35].

Metal ions and their coordination with polyphenols

Metal ions are indispensable core building blocks in MPNs, and their roles are not only reflected in providing coordination crosslinking sites, but also in determining the assembly behavior, physicochemical properties and biological functions of materials. Metal ions participate in regulating key physiological processes, including intercellular communication, maintaining charge and osmolality balance, electron transport, and DNA transcription regulation [36, 37]. Consequently, metal ions have been widely exploited in disease diagnosis and therapy in recent years, demonstrating significant application value in nanomedicine fields such as tumor therapy, bioimaging, antibacterial, angiogenesis, and bone tissue repair [38–42]. Within MPNs systems, commonly employed metal components primarily include main group metals, transition metals, and lanthanide metals. MPNs can form complexes with different stoichiometry (for example, single -, double -, triple - complexes), which can be modulated by various factors including pH, metal ion valence, and the molar ratio of metal ion to phenolic group [43]. Conversely, the species of metal ions and their associated stoichiometry guide the properties of MPNs. In addition, the choice of metal ions can determine the functional behavior of MPNs. Thus, in MPNs, metal ions are not merely passive structural crosslinking nodes but rather critical factors dictating material performance and functional behavior.

Recent studies have demonstrated that the coordination between polyphenols and metal ions in MPNs can occur through a variety of mechanisms, primarily including cation-π interactions, coordination bonds, redox reactions, and dynamic covalent bonds (Fig. 3). Cation-π interactions were first proposed by Dougherty et al., who found that electron-rich π systems, such as aromatic rings in tyrosine and tryptophan, can provide effective binding sites for alkali metal ions [44]. The interaction occurs between the metal ion and the aromatic ring of the polyphenol, which belongs to the electrostatic interaction, and its bond strength is affected by the electron density of the aromatic group of the polyphenol. Notably, the strength of cation-π interactions is also influenced by the type of metal ions, as demonstrated by studies on alkali metal ions (e.g., Li⁺, Na⁺, K⁺), alkaline earth metal ions (e.g., Mg²⁺, Ca²⁺), and transition metal ions (e.g., Ag⁺, Cu²⁺), which revealed that the interactions involving alkali and alkaline earth metal ions are generally stronger than those involving transition metals [45]. Coordination bond is another essential interaction mode, in which the electron pair of the polyphenol ligand fills the empty orbital of the metal ion to form the metal-polyphenol coordination structure. The dissociation kinetics of MPNs vary significantly with the metal ion species. Furthermore, the electronic structure of metal ions can govern their color properties. Multivalent metal ions with partially filled d-orbitals (e.g., Fe³⁺, Ti⁴⁺, Mn²⁺) frequently form dark MPNs due to the d-d electron transition. However, the main-group metal ions with completely empty or fully occupied d/f orbitals (e.g., Al³⁺, Ga³⁺, and In³⁺) mostly form light-colored MPNs [46]. This property paves the way for designing materials with tailored colors. Redox reactions are more common in the interaction between polyphenols and noble metal ions, such as Au³⁺, Ag⁺, etc. Noble metal ions can oxidize catechol groups in polyphenols to form semiquinone or quinone structures while themselves being reduced to the metallic state [47]. Dynamic covalent bonds represent another significant binding mechanism, especially in the interaction between metalloid elements (such as B, Si, Ge and other elements with both metallic and non-metallic properties) and polyphenols [48]. A typical example is the reversible formation of borate ester bond between boric acid and polyphenol o-diol structure, through which a dynamic responsive covalent cross-linking network can be constructed [49].

Fig. 3.

The interaction methods between polyphenol and metal ions

It is noteworthy that the type of metal ion not only influences the coordination mode but also further determines the functional performance of MPNs. Therefore, the essence of MPNs is not a simple combination of “metal + polyphenol”, but rather a programmable materials platform collectively governed by the chemical properties of the metal ions, the molecular structures of the polyphenols, and their mutual interaction patterns. A systematic understanding of the selection principles of metal ions and their coordination rules with polyphenols is of fundamental significance for the rational design and biological function regulation of MPNs in the future.

Representative synthesis method of MPNs

MPNs, with their unique physicochemical properties, have promoted the rapid development of a variety of MPNs-based composites and shown broad application prospects in many fields. Compared with the complex synthesis process of other nanomaterials, the preparation process of MPNs is simple, fast, environmentally friendly, and has good sustainability. The assembly mechanism is mainly based on the coordination between positively charged metal ions and electron-rich phenolic hydroxyl groups in polyphenols, which is significantly regulated by external conditions such as pH and temperature [43]. Notably, different assembly methods significantly influence the particle size distribution, morphological characteristics, pore/cavity structure, compositional tunability, and cargo loading capacity of MPNs, thereby largely determining their applications such as drug delivery, bioimaging, catalysis, and tissue regeneration [50]. Moreover, these assembly methods further affect the structural stability, degradation rate, release behavior of active components, and the ultimate biological functional output of MPNs in physiological or pathological environments.

Direct self-assembly

One-step synthesis is the most extensively used method for preparing nanoparticles at present, and it is also the easiest way to prepare MPN. The solution of polyphenols or their derivatives can be simply mixed with different metal ions in one pot. Due to the coordination driving force between metal ions and polyphenol ligands, it can be rapidly assembled to form nanoparticle complexes. The shape and size of the MPN are controlled by adjusting the proportion of the components, and its function depends on the composition. Caruso et al. in 2013 developed a one-step method to synthesize the complexes of tannic acid (TA) and Fe³⁺ ions that could be deposited in various templates including organic, inorganic, and biological particles (Fig. 4a) [51]. In addition, Sm³⁺-EC nanoparticles were synthesized by Li et al. in 2018 [52]. During the synthesis of Sm³⁺-EC self-assembled nanoparticles, the solutions of lanthanide samarium (Sm³⁺) ions and (-)-epicatechin (EC) were simply mixed at room temperature for 24 h stirring under neutral pH (Fig. 4b). The as-prepared Sm³⁺-EC nanoparticles exhibited an average size of 50 nm using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) (Fig. 4c). Sm³⁺-EC nanoparticles showed an effective therapeutic treatment of colon cancer. At the same time, Sm³⁺-EGCG nanocomplexes were also fabricated by self-assembled method using (–)-epigallocatechin-3-gallate (EGCG), and Sm³⁺ as building blocks [53]. Sm³⁺-EGCG nanocomplexes had a nearly spherical shape with a hydrodynamic average size about 61.2 ± 2.1 nm, which could inhibit melanoma tumor via regulating the metabatic pathways. Additionally, drugs containing polyphenol structures can also construct MPNs with metal ions to improve polyphenol utilization. For example, 1,4-bis-([2-{dimethylamino-N-oxide}ethyl]amino)5,8-dihydroxy-anthracene-9,10-dione (AQ4N) and gossypol could co-coordinate with Cu²⁺ by self-assembly method [54]. In the synthesis process, the ethanol solutions of gossypol, AQ4N, and CuCl₂ were quickly mixed in ethanol at pH = 7.4 and stirred for 6 h at room temperature. The AQ4N-Cu²⁺-gossypol nanoparticles were obtained after washed with water for several times and centrifugation. Afterwards, the curcumin-Fe³⁺ nanoparticles were prepared using the similar approach [55]. Xu and co-workers fabricated a library of MPNs nanoparticles with various compositions using directly assembled method at ambient temperature [56]. This study found that the kind of buffer (e.g., phosphate buffer) affected the formation of MPNs, and that the diameter and morphology of MPN NPs were adjusted by the reaction time, precursor concentration, and different pH values.

Fig. 4.

(a) The representative images of Fe^III-TA, which including (A) Images of PS slides before (top) and after (bottom) Fe^III-TA coating. (B to K) Microscopy images of Fe^III-TA capsules: DIC images [(B), (I), and (J)], AFM images (C), TEM images [(E), (F), (G), and (K)], SEM image (D), and fluorescence microscopy image (H). (b) Schematic diagram of the self-assembly of Ec-Sm nanoparticles. (c) SEM, EDS mapping, and HAADF images of Ec-Sm nanoparticles. (d) Schematic diagram of the prepartion of b-MPN nanoparticles

In addition, the polymers and biomacromolecules can be applied to stabilize MPN during the synthesis process. Liu et al. synthesized Fe-CPNDs using an easy method based on coordination between Fe³⁺ and gallic acid (GA) with poly(vinylpyrrolidone) (PVP) assistance [57]. During the prepare process, Fe³⁺and PVP were firstly mixed to generate PVP- Fe³⁺ complex. Then the GA was added into the solution of PVP- Fe³⁺ complex to form the Fe-CPNDs. PVP could spatially stabilize the Fe-CPNDs owing to the low coordination capacity of amide portion of PVP with Fe³⁺. Afterward, Chen et al. also fabricated Fe³⁺/GA/PVP nanoparticles (FGPNs) using coordination reactions among Fe³⁺, GA and PVP in aqueous solutions for multimodality imaging and photothermal therapy [58]. Bovine serum albumin (BSA) was also used to adjust the preparation of MPN [59, 60]. In 2021, Chen et al. constructed various bioactive nanoparticles (b-MPN NPs) through one-pot assembly of polyphenols, metal ions, and biomacromolecules (Fig. 4d) [61]. In this study, the polyphenols stabilize the b-MPN NPs through hydrophobic interactions and coordination, in which poly(ethylene glycol) (PEG) acted as a seed agent for the assembly. Overall, the prominent advantage of the direct self-assembly method lies in its mild reaction conditions and simple steps, making it suitable for constructing complex functionalized nanoparticles. Meanwhile, due to the spontaneity of the self-assembly process, its production cost is lower, demonstrating broad prospects in industrial applications. However, this method is sensitive to conditions such as the buffer system, pH, precursor concentration, and reaction time. Different assembly parameters directly affect the coordination state, nucleation behavior, particle size distribution, and colloidal stability. Therefore, it is relatively limited in precisely constructing complex hierarchical structures, regular hollow structures, or highly uniform pore structures.

Template-directed self-assembly

Template-assisted self-assembly is a commonly employed method for the fabrication of MPN nanocapsules. The process typically involves two key steps. The first step is the deposition of MPN precursors onto the surface of a sacrificial template, including polystyrene particles, CaCO₃ particles, mesoporous silica nanoparticles (MSN), or metal–organic frameworks (MOFs), to achieve interlocking and synergistic interparticle assembly [62, 63]. The second step is the selective etching of the template using a suitable solvent, such as hydrofluoric acid, ethanol, or ethylenediaminetetraacetic acid (EDTA), to obtain hollow MPN capsules. The morphology of the resulting structures is dictated by the shape of the template employed. The resultant capsules feature selective permeability, mechanical stability, and pH-responsive behavior, enabling encapsulation of core components within a protective barrier and thereby significantly enhancing carrier stability [64]. For example, Guo et al. synthesized an extensive library of functional MPNs through TA and a variety of metals by using polystyrene microspheres templates (Fig. 5a) [65]. The functional MPNs could be used to a broad application, such as magnetic resonance imaging (MRI), drug delivery, positron emission tomography (PET), and catalysis. CaCO₃ particles have also been used as templates for the synthesis of MPNs due to their ease of preparation, controlled morphology and easy removal. For example, Ju et al. developed nebulized Fe³⁺-TA capsules using the CaCO₃ sacrificial templates for controlled pulmonary deposition [66]. In order to prepare Fe³⁺-TA capsules, CaCO₃ nanoparticles were firstly synthesized with an average size of 1.1 ± 0.3 μm. Iron(III) chloride hexahydrate (FeCl₃·6H₂O) and TA solution were subsequently added to the dispersive of CaCO₃ particles, resulting in formation of Fe³⁺-TA complexes. The CaCO₃ template was finally removed with EDTA solution (100 mm, pH 7.5) and washed with water to obtain Fe³⁺-TA capsules. In another study, mesoporous MPN nanoparticles was fabricated using polymer cubosomes (PCs) as sacrificial template [67]. The PCs were self-assembled under water and dimethylformamide/dioxane mixture. EGCG was dispersed into the pores of PCs and followed coordinate with Fe³⁺ in situ (Fig. 5b). The PCs template was subsequently removed by tetrahydrofuran to form mesoporous MPN nanoparticles. The uniform tetragonally distributed pores were observed on the surface of mesoporous MPN nanoparticles. Another example of MPN microcapsules using PCs as a sacrificial template was designed by Chen et al. for programmable permeability [68]. ZIF-8 nanospheres were also used to as a self-sacrificial template to fabricate hollow nanoparticles. Qin et al. reported TA-Fe/Cu nanocapsules using ZIF-8 as self-sacrificial template through one-pot coordination of Fe³⁺/Cu²⁺ and TA, which efficiently improved diabetic infected wound healing with excellent photothermal ability, antibacterial, anti-inflammatory, and angiogenesis [69]. During the formation of TA-Fe/Cu, the ZIF-8 template was removed in an acidic environment, leading to formation of hollow spherical nanoparticles. Tardy et al. designed a method to synthesize the MPN capsule using lignin nano-microparticles as readily degradable template [70]. Fe³⁺ and TA solutions were dispersed in the suspension of lignin particles, and in situ assembled on its surface. Finally, the lignin template was eliminated by sodium phosphate solution to capture functional MPN capsules. In conclusion, compared with direct self-assembly, the template-directed self-assembly method offers a significant advantage in shape designability, making it particularly suitable for constructing hollow, mesoporous, core-shell or programmable permeable MPN structures. Therefore, it has more advantages in applications such as high drug loading, controllable release, and drug delivery.

Fig. 5.

(a) Assembly of TA and metal ions into an MPN film on a particulate template, followed by processing into an MPN capsule. (b) A schematic diagram of the preparation of MPN particles using PCs as a template. (c) Schematic diagram of the sol-gel synthesis strategy for Cu-PTA NPs. (d) Morphological characterization of PTA and Cu-PTA NPs

Sol-gel method

A variety of inorganic and organic nanospheres have been prepared based on sol-gel method. In 2018, a formaldehyde-assisted metal-ligand cross-linking strategy was reported for the synthesis of MPN of uniform diameter (about 300 nm) and adjustable composition by Wei and co-workers [71]. The formation of MPNs involved pre-crosslinking TA with formaldehyde in an alkaline ethanol/water solvent, followed by aggregative assembly of polyphenol oligomers and metal ions by metal-ligand crosslinking. This MPNs could be used for sensitive analysis as sensing platforms, which had significant applications in biomedical and electrochemical devices. In addition, copper-poly (tannic acid) nanoparticles (Cu-PTA NPs) were fabricated via sol-gel assisted assembly method by Li et al. for infected wound therapy [72]. PTA NPs were firstly prepared using the sol-gel method with formaldehyde assistance. Then, the Cu-PTA NPs were fabricated through metal-ligand crosslinking between Cu²⁺ and PTA solution under hydrothermal treatment (Fig. 5c). The morphology of PTA and Cu-PTA NPs was uniform spheres with the average size of 71.08 and 138 nm, respectively (Fig. 5d). It is more interesting that independent nanospheres are formed only after the coordination of Cu and PTA oligomers. Cu-PTA NPs showed an enhanced infected wound repair by regulating wound microenvironment, antioxidative, antibacterial, and anti-inflammatory. Bimetallic MPN colloidal spheres were synthesized by adjusting the type and proportion of metal precursors. Qin et al. reported Gd/Fe-bimetal-phenolic coordination nanoparticles through coordination assembly method under alkaline environment using gadolinium nitrate and ferrous sulphate as a metal source, and TA as organic ligand [73]. TA was firstly reacted with formaldehyde to form TA- formaldehyde oligomers, and then a certain amount of bimetal-source was introduced into the oligomers to further crosslink via metal-catechol coordination bond. The content of Gd and Fe in MPN can be easily adjusted by changing the molar ratio of metal source to tannic acid during synthesis, thus regulating the relaxation and photothermal properties. Afterward, a series of iron-polyphenol nanoparticles were synthesized through sol-gel method by Qin and co-workers based on five polyphenols as a ligand, containing TA, epigallocatechin gallate (EGCG), gallic acid (GA), epicatechin (EC) and proanthocyanidin (PC) [74]. Iron-polyphenol nanoparticles showed a tunable diameter (21–303 nm) with adjustable iron content, which could play a vital role in cancer therapy. Overall, the sol-gel method is better suited for constructing coordination colloidal spheres with uniform morphology and precisely adjustable composition, particularly for the preparation of single-metal, bimetallic, and even multimetallic MPN systems. This advantage primarily stems from the prepolymerization process of the phenolic molecules, which contributes to the formation of a more stable colloidal framework and offers greater flexibility in regulating the metal content and compositional ratio.

Properties of MPNs in enhancing tissue regeneration

MPNs are composed of polyphenol ligands and metal ions, which exhibit diverse functional properties. The properties of MPNs are determined by the specific types of polyphenol ligands and metal ions. In general, the final properties of MPNs can be precisely regulated by the selection and combination of metal ions and polyphenol types. Therefore, it is of great significance to systematically summarize and classify these functional properties based on different components for promoting the targeted design and application of MPNs.

Adhesive property

Mussel-like adhesive materials are a kind of structural units rich in catechetic functional groups and have excellent adhesion properties. Among them, 3,4-dihydroxyphenylalanine (DOPA) is a typical catechol derivative. The catechol groups in its molecular structure can adhere to the surface of a variety of materials in complex environments such as humidity, high salt and fluid shear. Similarly, natural polyphenolic compounds (such as tannic acid, gallic acid, epigallocatechin gallate, etc.,) due to their rich catechol/pyrogallol structure, not only possess significant metal chelation, protein binding and antioxidant capabilities, but also exhibit excellent interfacial adhesion properties [75]. It can strongly bind to a variety of biological or abiotic surfaces and endow a variety of functions to the substrate material.

The adhesion of polyphenols is mainly due to a variety of non-covalent interactions with their interfaces, including hydrogen bonding, π-π stacking, electrostatic interaction, hydrophobic effects, and van der Waals forces [76]. This multiple mechanism also enables efficient binding of polyphenols to proteins, nucleic acids (e.g., DNA and RNA), and other biomolecules. Notably, the adhesion behavior of MPNs can be effectively modulated by the selection of polyphenol ligands with different chemical structures. Based on this characteristic, MPNs can take advantage of their excellent adhesion properties to combine functional components with substrate materials, and realize the synergistic integration of structure and function, which provides a broad prospect for the design and construction of high-performance composite materials. For example, MPNs could easily coating on two dimensional nanomaterials, such as graphene, graphene oxide (GO) and reduced graphene oxide (rGO). Ozawa et al. developed a new nanosheet using Fe-TA film coting on the GO sheets, which had the good stability in water [77]. In addition, the MPNs can be coated on the bacterial, cells, yeast, and viruses, owing to their high biocompatibility. In spired by the viscosity of the MPNs in biostructures, Li et al. fabricated an artificial shell by cross-linking of iron ion and TA on the surface of the cells, which could protect the cells against UV light irradiation and ROS damage [78].

Stimuli-responsive property

Another important feature of MPNs is their stimuli-responsive behavior, which is closely related to the dynamic and reversible nature of metal–phenolic coordination. In tissue repair, this property is particularly valuable because regenerative microenvironments are highly heterogeneous and often evolve over time. Accordingly, MPNs can be activated by pH, ROS, and near-infrared (NIR) irradiation. The precise characteristics of these stimuli-responsive behaviors are dictated by a combination of factors, including the selection and valence of the metal ions, as well as their molar ratio relative to polyphenolic components. pH responsiveness is the most classic endogenous mechanism of MPNs, fundamentally arising from the instability of metal-phenolic coordination bonds under acidic conditions. The interaction between phenolic ligands and metal ions in MPNs is influenced by pH, and the stability of their coordination bonds varies under different pH conditions [79]. Under acidic conditions, the protonation of phenolic hydroxyl groups weakens their coordination ability with metal ions, leading to the dissociation and degradation of the MPN structure. In contrast, under neutral or alkaline conditions, the coordination remains relatively stable. It is generally observed that high-valence metal ions (e.g., Zr⁴⁺ and Fe³⁺) exhibit a greater propensity for chelation with polyphenols than lower-valence species (e.g., Cu²⁺ and Fe²⁺) [80]. Furthermore, the stoichiometric composition of the MPNs is a key determinant of its acid-responsive characteristics. Specifically, an increase in metal content correlates with a decrease in acid sensitivity, a phenomenon attributed to the elevated coordination degree which reinforces structural stability [81]. Ding et al. developed a pH-responsive antibacterial MPNs coating on hernia meshes, which was consisted of Cu²⁺ and TA (called to CT coating) [82]. The release behavior of both Cu²⁺ and TA from the CT coatings was highly sensitive to pH. Relative to the release at pH 7.4, the amount of Cu²⁺ released from all coatings increased correspondingly at pH 5.5. Similarly, while only a small amount of TA was released at pH 7.4, its release significantly increased under acidic conditions (pH 5.5). These results demonstrate that the prepared CT coatings possess excellent pH-responsive controlled release properties. This pH-sensitive release behavior is particularly meaningful for regenerative systems because it allows pathological tissues to trigger faster ion liberation than healthy tissues. In addition, disease-associated oxidative or inflammatory microenvironments may also destabilize coordination networks and facilitate active-component release. Zhou et al. developed a microenvironment-responsive metal-phenolic release platform for intervertebral disc degeneration, in which pathological conditions triggered network disassembly, ROS scavenging, pyroptosis suppression, and extracellular matrix preservation [83].

Furthermore, MPNs exhibit ROS responsiveness, enabling them to selectively disassemble in oxidative stress microenvironments characterized by overexpression of ROS. Chen et al. developed a ROS- and pH-responsive zinc-gallic acid nanosheets (ZnGA NSs) for diabetic wound healing [84]. In this study, the ZnGA nanospheres demonstrated dual-responsive release behavior. In the presence of 3 mM H₂O₂, the cumulative Zn²⁺ release reached 26.12 µg/mL over 7 days, significantly higher than the 8.62 µg/mL released in the absence of H₂O₂. The system also exhibited pH-dependent release kinetics: at pH 5.5, both Zn²⁺ (9.61 µg/mL) and GA (18.52 µg/mL) were released more rapidly within 24 h compared to pH 7.4 (Zn²⁺: 4.3 µg/mL; GA: 11.83 µg/mL). This enhanced release under acidic conditions is attributed to the increased protonation of phenoxy groups in ZnGA, which weakens coordination bonds and accelerates ion and ligand dissociation. Another study has elucidated that while MPNs preserve their structural integrity within physiological milieus, they are susceptible to targeted degradation upon exposure to elevated ROS concentrations. Leveraging this property, Cu²⁺/TA nanoparticles were engineered to exhibit a precisely modulated release kinetics specifically orchestrated by ROS stimuli [72]. In summary, MPNs enable the on-demand release of metal ions and polyphenols, thereby orchestrating a dynamic equilibrium between oxidation and antioxidation to maintain microenvironmental homeostasis.

In addition, due to their unique structural and functional characteristics, MPNs demonstrate significant potential in the field of photothermal conversion. The photothermal conversion capability of MPNs primarily originates from the metal ions and polyphenolic ligands within their structure [85]. Metal ions, such as Fe³⁺ and Al³⁺, can absorb light at specific wavelengths and convert it into heat. Polyphenolic ligands, including EGCG and tannic acid (TA), not only provide coordination sites but also exhibit strong light absorption due to the conjugated systems within their molecular structures. The photothermal conversion efficiency of MPNs is influenced by multiple factors, including the type of metal ions, the structure of the polyphenolic ligands, and the size and morphology of the MPNs [86]. In recent study, Ye et al. prepared EGCG-functionalized gold nanoparticles (E-Au NPs) by coordinating tea polyphenols with Au³⁺. Under NIR light, these nanoparticles effectively inhibited biofilm formation in drug-resistant bacteria [87]. In addition, In t-P@TFP nanoparticles was synthesized by Chen at al. for combating against multidrug resistance and metastasis [88]. In this study, on NIR laser irradiation, t-P@TFP nanoparticles undergo a photothermally-triggered cascade, where phase transition of perfluoropentane disrupts the TA-Fe³⁺ shell and accelerates drug release.

In summary, the inherent stimuli-responsive properties of MPNs enable them to undergo dynamic structural and functional adaptations in response to complex environmental fluctuations, thereby broadening their utility and translational potential in biomedical applications.

Antioxidant, anti-inflammatory and immune regulatory properties

The MPNs exhibit a wide range of functions in antioxidant, anti-inflammatory, and immune regulation. The sources of reactive oxygen species (ROS) in the body are diverse, mainly produced by the mitochondrial respiratory chain, exogenous stimuli, and metabolic processes in organelles such as peroxisomes and endoplasmic reticulum. Significantly elevated ROS levels trigger an inflammatory response, leading to severe damage to cellular structures [89]. Therefore, scavenging excessive ROS has become one of the important strategies to prevent and treat inflammation. With their strong antioxidant capacity, polyphenols can effectively scavenge free radicals and reduce oxidative stress. They inhibit inflammation by simultaneously targeting ROS and reactive nitrogen species (RNS) to protect cells from oxidative damage. In addition, the chelation of polyphenols with metal ions not only improves their bioavailability, but also further enhances the scavenging efficiency of ROS. EGCG is the primary component of green tea, which possesses intrinsic antioxidant properties with higher antioxidant activity than vitamins C and E. Consequently, MNPs composed of EGCG have free radical scavenging properties. Chen et al. developed an EGCG-Mn nanoparticles with reactive oxygen and nitrogen species (RONS) scavenging performance [90]. EGCG-Mn nanoparticles could effectively scavenge free radicals such as DPPH•, ABTS+•, •OH, •O₂⁻, and •NO. At the same time, they also have good RONS scavenging activity at the cellular level and protect cells from oxidative damage. Tannic acid (TA) is effective in removing reactive oxygen species due to its catechol group by the mechanism that isolated hydrogen atoms in the catechol group can combine with ROS to form harmless O₂ and H₂O. Therefore, Wei et al. reported a series of metal-TA nanoenzymes (M-TA NMs) that could alleviate the oxidative stress response [91]. Due to the tunable center of catalytic activity, M-TA NMs exhibited adjustable antioxidant activity against a variety of RNOS. TA NMs had the best DPPH radical removing capacity, because TA NMs had free phenolic hydroxyl group which could directly reduce DPPH, while the other metal-polyphenol nanozymes required dissociation of coordination bonds or cation-π interactions before DPPH interaction. Remarkedly, Cu-TA NMs could simulate the SOD and CAT cascade process to maintain intracellular redox homeostasis, which exhibited the best scavenging capacity (Fig. 6a). In addition, TA was coordinated with europium (Eu) to form TA-Eu nanoparticles, which also exhibited excellent ROS scavenging ability. The ROS scavenging ability of TA-Eu was enhanced with increasing concentration and showed better scavenging ability in acidic environment (pH = 5), which was able to release more TA from TA-Eu [92]. Rosmarinic acid (RosA) is a kind of polyphenol that can also form MPNs through coordination interaction with metal ions. Yuan et al. designed a RosA-Mn nanoparticles, which showed cascade antioxidant capacity. The broad-spectrum radical scavenging activity of RosA-Mn at different concentrations was systematically investigated. The results confirmed that RosA-Mn had good scavenging ability for 2,2 ‘-diazo (3-ethylbenzothiazole-6-sulfonic acid) diammonium salt (ABTS),1, 1-diphenyl-2-decyl hydrazine (DPPH), hydroxyl radical (•OH) and superoxide anion radical (O₂) •⁻ [93].

Fig. 6.

(a) Schematic representation of RNOS scavenging by M-TA nanomaterials. (b) Schematic illustration of the synergistic ROS scavenging, inhibition of macrophage M1 polarization, and anti-inflammatory action by Cu-EGCG nanosheets

Macrophages play a central role in inflammation regulation — as the first effector cells in the inflammatory response, they mediate the inflammatory cascade by secreting pro-inflammatory cytokines (such as IL-1β, TNF-α, IL-6) and inflammatory mediators (such as NO, iNOS) [94]. However, the excessive release of cytokines and inflammatory mediators can disrupt homeostasis, leading to cellular and tissue-level damage. It is noteworthy that inflammation also plays a dual role in tissue repair: it promotes repair through mechanisms such as clearing damaged products and releasing growth factors, while requiring vigilance against pathological transitions to chronic inflammation or fibrosis when regulation is imbalanced [95]. MPNs demonstrate unique advantages in regulating macrophage polarization due to their ROS clearance ability. Studies have confirmed that EGCG exhibited significant anti-inflammatory biological activity [96]. On the one hand, EGCG can induce phenotypic switching of macrophages, promoting the polarization of pro-inflammatory M1 type to anti-inflammatory M2 type, while inhibiting the adhesion and migration of neutrophils. On the other hand, as a potent antioxidant, EGCG can efficiently ROS in vivo. By alleviating the activation effect of oxidative stress on inflammatory signaling pathways, it further reduces the release of pro-inflammatory cytokines such as IL-1β and TNF-α, ultimately achieving the biological effect of multi-target collaborative anti-inflammation [97]. For example, Wei et al. synthesized Cu-EGCG nanosheets for alleviating chondrocytes inflammation, which showed excellent antioxidant and anti-inflammatory behaviors (Fig. 6b) [98]. Cu-EGCG nanosheets effectively scavenged excessive intracellular ROS, leading to a significant reduction in the expression of pro-inflammatory cytokines. It could also reduce the expression of M1-type macrophages and promote the conversion of macrophages to M2-type phenotype. Subsequently, Duan et al. used copper ions and EGCG to coat M2 macrophages, which improved cell survival, while also enriching the function of the Cu-EGCG system with cell function. Due to its good anti-inflammatory and pro-angiogenic ability, it can effectively treat critical limb ischemia [99]. In addition, MPNs formed by the coordination of iron ions and EGCG, also had promising anti-inflammatory activity and could be applied to the treatment of inflammation-related diseases [100]. Curcumin (Cur) is a polyphenolic substance extracted from turmeric, which has excellent pharmacological effects, such as hypolipidemic, antioxidant and anti-inflammatory. The nanocomplexes (Fe-Cur) formed by Cur and Fe have the properties of nanoenzymes, which could clear intracellular ROS and had great anti-inflammatory ability. The results showed that Fe-Cur exerted anti-inflammatory effects through inhibiting the secretion of TNF-α and IL-6, NLRP3 inflammasome and NF-κB pathway [101]. Chlorogenic acid (CA), a bioactive polyphenol found in many plants, fruits and vegetables, acts as a natural antioxidant, which could also coordinate with metal ions to form MPNs. Wang et al. constructed CA-Mn nanozymes through the self-assembly process of CA and manganese ions for reduce inflammation in acute liver injury [102]. The results indicated the anti-inflammatory mechanism of CA-Mn NPs was the up-regulation of Nrf2-Keap1 signaling pathway and the down-regulation of NF-κB p65 pathway. In addition, CA-Mn NPs could restore the autophagic function of macrophages and transformed M1 macrophages into M2 macrophages.

The immunoregulatory function of MPNs is not limited to macrophages alone, but extends to a broader range of immune cell populations. Numerous studies have demonstrated that phenolic compounds can modulate the differentiation and maturation of dendritic cells, inhibit oxidative stress in neutrophils, and regulate the differentiation and function of T cells, thereby exerting broad-spectrum immunomodulatory effects. Regulatory T cells (Tregs) suppress immune responses and promote tissue repair. Current research indicates that dihydromyricetin (DHM) and copper ions form Cu-DHM nanoparticles that synergistically regulate macrophage polarization and cytokine release, cascade and amplify the immunomodulatory interplay between M2-type macrophages and naive CD4⁺ T cells, and promote the conversion of Th17 cells to Treg cells, effectively ameliorating the local immune microenvironment [103]. Furthermore, Cu-DHM nanoparticles inhibit apoptosis, reduce neutrophil infiltration in flap tissue, alleviate inflammatory responses, and promote angiogenesis. These results indicate that MPNs can systematically reshape the immune microenvironment by regulating the level of ROS, thereby creating favorable conditions for tissue repair.

Antibacterial

MPNs also has good antibacterial ability due to their unique properties of polyphenols and metal ions. The antibacterial effect of MPNs is achieved by the released metal ions or polyphenols or the synergistic effect of both. At present, the widely accepted antibacterial mechanisms of MPNs include :1) disruption of bacterial cell membranes through the release of metal ions; 2) generating reactive oxygen species (ROS) to destroy bacteria and their biofilms; 3) interacting with proteins, peptides, DNA and other substances, destroying and affecting their functions [27]. Many metal ions have shown excellent antibacterial effects, but their application is limited due to their high toxicity. In recent years, the introduction of polyphenolic compounds to form MPNs with metal ions has reduced the adverse cytotoxicity and genotoxicity caused by metal ions, which greatly improved the biocompatibility of MPNs, and provided the possibility to design safer and more effective biomedical materials. For example, nanosilver modified with gallic acid (GA@AgNPs) has abundant carboxyl groups, which could coordinate with divalent ions to form ionic bonds with sodium alginate. The silver nanoparticles were strongly immobilized in the hydrogel, and the Ag⁺ could be gently released from the GA@AgNPs-SA hydrogels. The antibacterial experiments showed that the GA@AgNPs-SA hydrogel had good long-term effective and sustained antibacterial effect compared with the AgNPs-SA hydrogel, while showing good cell and blood compatibility [104]. When polyphenols were prepared as constituent structures with metal ions to obtain MPNs, the polyphenols could enhance the Fenton reaction by reducing metal ions in high oxidation states to metal ions in low oxidation states, thereby increasing the reutilization of the metal ions, which in turn generated more ROS that could cause damage to bacteria. EGCG has been reported to react with dissolved oxygen in alkaline aqueous solutions, acting as a pro-oxidant and autoxidizing to form H₂O₂ [105]. Based on this, Chen et al. reported a series of metal-EGCG network to investigate the antioxidant activity or oxidative effect of EGCG at physiological pH [106]. The experimental results showed that Ni²⁺ exhibited a good ability to promote H₂O₂ generation. Even under neutral conditions (i.e., pH 7), Fe ³⁺ accelerated the ability of Ni²⁺ -EGCG to decompose H₂O₂. With the production of •OH, Ni²⁺ -EGCG@Fe³⁺ showed great advantages in bactericidal efficacy and biofilm removal in gram-negative bacteria Escherichia coli (E. coli) and Pseudomonas aeruginosa (PAO1). In addition, the introduction of carboxylic acid into the phenolic/Fe network could effectively control the peroxidase-like activity of the phenolic/Fe through the acidic microenvironment and the proximity effect of the carboxyl group. Thus, the carboxylate-containing gallic acid/iron (GA/Fe) nanoparticles had the ability to catalyze the generation of oxidative radicals from H₂O₂, disrupt bacterial membranes and induce intracellular ROS generation to effectively kill Streptococcus mutans. In the presence of carboxyl groups, the Fenton reaction was accelerated, increasing the overall radical generation rate. The catalytic performance of MPNs was further elaborated by theoretical calculations that adjacent carboxyl groups could enhance the catalytic performance of GA/Fe [107]. In addition, the CuTA nanozymes synthesized by the Cu and TA collaborative self-assembly strategy also possessed antimicrobial activity [108]. The antimicrobial capacity of CuTA varied with concentration. The possible combined antibacterial mechanisms of CuTA were as follows: (1) The needle-like structure of CuTA interacted with bacteria and destroyed the cell membrane; (2) CuTA efficiently produced ˙•OH in the presence of H₂O₂, resulting in oxidative damage to cells. (3) CuTA could also act as a GSH-OXD-like nanoenzyme to comsume GSH in the internal environment of E. coli and enhanced the efficacy of antimicrobial therapy (Fig. 7a). Therefore, this study suggested that CuTA showed strong antibacterial activity, providing an effective strategy for antibacterial. In addition, some MPNs have good photothermal conversion performance in near-infrared light irradiation. Photothermal therapy can destroy the integrity of pathogens through non-invasive light-induced localized thermal therapy. High temperatures can inactivate biologically active substrates inherent in biofilms (e.g., enzymes, nucleic acids, and proteins), thus disrupting the biofilm’s physiological environment to kill the bacteria [86]. Chen at al. constructed novel Pd based MPNs with oxidase-like and photothermal performance to eradicate bacterial biofilm [109]. In this study, the •O²⁻ produced by MPN-Pd could kill Streptococcus mutans and Enterococcus faecalis in an oxidase-like property-dominated manner. In addition, Candida albicans was more sensitive to MPN-pd-mediated thermotherapy, and could be eradicated by photothermal effect. Taken together, MPNs could be used as a good antibacterial agent to treat bacterial infection-related diseases.

Fig. 7.

(a) The antibacterial capacity of CuTA. (b) Angiogensis evaluation of the COC@SalB-Cu hydrogel

Angiogenesis

The formation of neovascularization or new blood vessels is essential for tissue repair. It provides oxygen, growth factors and immune support to the new tissue, which leads to cell proliferation and tissue regeneration [110]. The vascular endothelial growth factor (VEGF) family has been recognized as a key regulator of therapeutic angiogenesis that promotes endothelial cell survival, proliferation and migration. Many studies have reported that metal ions released from MPNs showed a great positive effect on VEGF formation [111]. For example, Cu-CGCG coordination network was designed for peripheral artery disease. In this regard, Cu ions could continuously release from Cu-CGCG, and biocompatible Cu-EGCG could scavenge intracellular ROS, decrease the expression of pro-inflammatory cytokines (TNF-α, IL- 6), and induce the secretion of VEGF. More importantly, the expression of platelet endothelial cell adhesion molecule-1 (CD31) and proliferating cell nuclear antigen (PCNA) was upregulated in ischemic tissues, further indicating the significant effect of Cu-EGCG on angiogenesis [62]. Later, they found that EGCG-Zn was also able to promote angiogenesis. In this study, EGCG-Zn facilitated the sustained release of zinc ions, which reduced cytotoxicity and enhanced VEGF secretion [112]. Salvianolic acid B (SalB), a biologically active polyphenolic compound in Salvia miltiorrhiza, could coordinate with Cu²⁺ to form nanozymes (SalB-CuNCs) with SOD-CAT cascade catalytic activity [113]. SalB-CuNCs could induce angiogenesis due to the intrinsic angiogenic activity of SalB and Cu²⁺, which were conducive to regulating endothelial cells to restore blood supply and oxygen supply (Fig. 7b). Subsequently, SalB-CuNCs were integrated into Schiff base hydrogels (COC@SalB-Cu), which induced more complete tube formation via up-regulating the expression levels of vascular related factors, including VEGF, platelet-endothelial cell adhesion molecule-1 (CD31) and endothelial nitric oxide synthase (eNOS).

Applications of MPNs for tissue regeneration

MPNs have showed various excellent properties in tissue engineering filed owing to their novel and unique structures, consisting of adhesion, antioxidant, anti-inflammation, antibacterial, and angiogenesis performance. Based on these excellent characteristics, MPNs have a very important role in the field of tissue repair, including skin, bone, cartilage, osteoarthritis, rheumatoid arthritis, heart, spinal cord, and other tissues (Table 1). The specific role of MPNs in tissue repair will be discussed in detail in this section.

Table 1.

Representative MPNS systems: synthesis, structural characteristics, and functional applications

Metal	Polyphenol	Synthetic material	Synthesis method	Key parameters	Structural characteristics	Biological function	Applications	Ref
Cu²⁺	TA	Cu-PTA	Sol–gel method	Mass ratio: 1:5 (CuSO4·5H2O: TA)	Nanoparticles (size: 138 nm)	Microenvironment-responsive, antibacterial, antioxidative, anti-inflammatory.	Infected wound healing	[72]
Eu3+	TA	PH/CuS/TA-Eu microneedles	Self-assembly	Mass ratio: 1:1 (Eu3+: TA) pH = 7	Nanoparticles (size: 24.70 nm)	Antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, angiogenesis.	Acute diabetic wounds	[92]
Cu2+	GA	Cu-GA	One-pot method	Mass ratio: 1.8:1 (Cu2+: GA) pH = 13	Nanorods (average size: 50 ± 10 nm)	Scavenge ROS, kill bacteria, control inflammation, promote angiogenesis.	Infected wound healing	[120]
Co²⁺	EGCG	THA-EGCG-Co hydrogel	Self-assembly	Molar ratio: 2:3 (Co2+: EGCG) (pH = 7)	Nanoparticles (Size:20 nm)	Antimicrobial, antibiofilm, Antioxidant.	Chronic wound	[124]
Zr⁴⁺	EGCG	Gel/Zr/EGCG hydrogel	/	/	/	Enhance cell migration, anti-inflammatory, antioxidant, reshape microenvironment	Diabetic wound	[125]
Ce4+	EGCG	EGCG@Ce Gel	Self-assembly	Molar ratio: 1:1 (Ce4+: EGCG) (pH = 8)	Complex (Size: 1 ± 0.14 μm)	Reducing RO, alleviating inflammatory, enhancing the M2 macrophage polarization, angiogenesis.	Full-thickness skin wounds	[126]
Cu²⁺	EGCG	SilMA/HAMA/Cu-EGCG hydrogel	CaCO₃ template- based self-assembly	Molar ratio: 1:1 (Cu2+: EGCG) (pH = 8)	Capsules (Size: 123.4 ± 5.3 nm)	Antibacterial, pro-angiogenic, anti-inflammatory.	Infected full-thickness skin wound	[127]
Mg²⁺	Tea polyphenols	TP-Mg@PSG	Self-assembly	Mass ratio: 144:1 (Mg2+: TP)	Nanoparticles (Size: 14.7 ± 4.2 nm)	Anti-MRSA biofilm, promoting cell proliferation, anti-inflammatory.	MRSA infected diabetes wound	[128]
Mg²⁺	Curcumin /	Cur-Mg@PP powder	Hydrothermal method	Mass ratio: 5:4 (Mg2+: Cur) (pH = 12)	Spherical structure (Size: 22 –5 μm)	Antioxidant, anti-inflammatory, angiogenesis, tissue regeneration.	Burn wound	[131]
Mg²⁺	EGCG	EGCG-Mg2 + coating on titanium alloy	Self-assembly	pH = 7	/	Osteogenesis, osseointegration, reduced osteoclast maturation	Osseointegration	[142]
Sr²⁺	EGCG	PMPNs@ECM/nHAW scaffolds	Self-assembly	Mass ratio: 1.6:1 (Sr2+: EGCG) pH = 8	Nanoparticles (Size: 499.88 ± 118.62 nm)	Antioxidant, anti-inflammatory, antibacterial, osteochondral regeneration.	Bone defect repair	[143]
Mg²⁺	TA	TMg-incorporating Cryogel	Self-assembly	/	Nanoparticles (Size: 316 ± 53 nm)	Angiogenesis, anti-inflammatory, osteoconduction.	Bone regenerative	[145]
Ce4+	EGCG	EGCG-Ce	One-step assembly	10 mM HEPES solution (pH = 7.4)	Nanoparticles (Size :13 ± 2 nm)	Relieving synovial inflammation, cartilage erosion.	Rheumatoid arthritis treatment	[160]
Fe3+	Qur	Fe-Qur	Self-assembly with PVP assistance	Mass ratio: 2.5:1 (Fe3+: Qur)	Nanodots (Size: ~ 5 nm)	Antioxidant, anti-inflammatory, avoid cell apoptosis, inhibiting osteoclasts.	Rheumatoid arthritis treatment	[161]
Cu²⁺	TA	Cig/(TA-Cu) scaffolds	Self-assembly	/	/	Conductive, antioxidative, angiogenic.	Myocardial infarction repair	[167]
Ce4+	TA	TA − Ce	One-step assembly	Molar ratio: 6:1 (Ce4+: TA) (pH = 7.4)	Nanoparticles (Size:95.43 nm ± 2.52 nm)	Scavenge excessive ROS, cardiomyocyte-targeting.	Ischemia/reperfusion injury therapy	[168]
Fe3+	PC	AuAg@PC-Fe	Self-assembly	Molar ratio: 1.5:1 (Fe3+: PC) (pH = 7.8)	/	Photothermal antibacterial, ROS scavenging, immunotherapy.	Bacteria-induced periodontitis	[183]
Cu2+	TA	TM/BHT/CuTA Hydrogel	Self-assembly	Mass ratio: 32:1 (CuSO₄·5 H₂O: TA) (pH = 7.4)	Nanosheets	Scavenge multiple ROS, modulate the macrophage polarization.	Periodontitis therapy	[184]
Ca2+	TA	CaTA@Gel	Self-assembly	Mass ratio: 32:1 (Ca(NO₃)₂·4 H₂O: TA) (pH = 7.4)	Nanoparticles (Size:64 ± 0.9 nm)	Anti-bacteria, ROS scavenging, osteogenesis.	Periodontitis therapy	[185]
Zn2+	GA	ZnGA	One-pot solvothermal method	Molar ratio: 1:50 (Zn2+: GA)	Nanoflowers	High bactericidal effect	MRSA-induced bacterial keratitis therapy	[187]
Zn2+	EGCG	EGCG-Zn	Self-assembly	Molar ratio: 1:1 (Zn2+: EGCG)	Nanoparticles	Scavenge ROS, anti-cell damage performance.	Cataract treatment	[192]

Skin wound repair

Wound healing is a fascinating biological process that consists of four major fundamental stages, including hemostasis, inflammation, proliferation, and remodeling. The disorder of molecular signaling or cell dysfunction in any link may cause the healing process to stall and evolve into chronic refractory wounds. Clinicians have long faced severe challenges in wound treatment. Chronic wounds, such as diabetic foot ulcers and pressure injuries, not only seriously reduce the quality of life of patients, but also bring heavy medical burden [114, 115]. Traditional wound treatment strategies include removing necrotic tissue of the wound through mechanical debridement, using functional dressings such as alginate and hydrogel to maintain a moist healing environment, and local application of growth factors to promote cell proliferation [116, 117]. Compared with traditional therapeutic drugs, MPNs have the dual properties of metal ions and polyphenols, which can bring into play the properties of each component to achieve antibacterial, anti-inflammatory, oxidative stress and pro-angiogenesis, and the two can interact with each other to achieve the therapeutic effect of “1 + 1>2” through a novel therapeutic pathway. The MPNs nanomaterials could be applied directly to trauma sites for wound repair [118, 119]. Tian et al. designed a copper-gallic acid (GA-Cu) nanorods for bacterial infected wound healing with multienzyme behavior including peroxidase, superoxide dismu-tase, and glutathione peroxidase [120]. GA-Cu nanorods could generate a lot of reactive oxygen species (ROS) to kill bacterial during acidic conditions, while removing ROS under neutral environment to promote wound repair. Furthermore, Chen et al. designed a pH/ROS dual responsive zinc-gallic acid nanosheets (ZnGA NSs) for diabetic wound healing. In this study, ZnGA NSs could exhibit sustained release of Zn²⁺ and GA under diabetic conditions, thereby accelerating wound repair. During the early phase of repair, the gradual release of Zn²⁺ promoted angiogenesis. Concurrently, GA could activate the antioxidant enzyme system via the KEAP1/NRF2 pathway and enhance mitochondrial fusion through the upregulation of MFN1/2 and OPA1, ultimately contributing to the reprogramming of dysfunctional fibroblasts. The robust antioxidant and angiogenic activities suggesting ZnGA NSs as promising candidates for diabetic wound therapy [84]. However, direct treatment of wounds with MPNs is hampered by poor solution stability, resulting in rapid release of metal ions, which hinders its long-lasting effects at multiple wound healing stages. To solve these issues, Li et al. developed copper-poly(tannic acid) nanoparticles (Cu-PTA NPs), which could hierarchically regulate infected wound healing with antibacterial and anti-inflammation (Fig. 8a) [72]. Compared with ordinary Cu-MPNs prepared by small-molecules as ligand, the Cu-PTA NPs showed improved stability and bioavailability with the dually crosslinked robust structures. Cu-PTA NPs showed ROS-responsive degradation and on-demand release of Cu²⁺ behaviors, significantly prolonged the antimicrobial period and reduced side effects, while had synergistic dual physical and chemical antimicrobial effects owing to in-situ adhesion and peroxidase (POD)-like activity in the infected microenvironment. By suppressing bacteria, promoting blood vessel growth, balancing free radical levels, and alleviating inflammation, Cu-PTA NPs could systematically promote infected wound healing. In addition, MPN can also be used as an active coating that wraps around the surface of nanomaterials to improve their properties for wound repair. Zhang et al. constructed a MPNs modified gold nanorods (GNRs@MPNs) through coordination, which improved the biocompatibility and photothermal conversion performance, and better promoted the healing of methicillin-resistant S. aureus. infected wounds (Fig. 8b) [86]. Subsequently, Fe²⁺-TA network coated on the kaolinite nanoclay and glucose oxidase (GOx) was reported for sterilization and infectious wound repair (Fig. 8c) [121]. The bio-clayzyme (Kaol@GOx@Fe-TA) showed cascading GOX and POD-like catalytic performance to form •OH for inhibiting bacterial. Moreover, Kaol@GOx@Fe-TA performed anti-inflammatory and hemostatic behaviors. In vivo animal experiment further confirmed that Kaol@GOx@Fe-TA could effectively accelerated wound regeneration through the hemostatic, antibacterial, and anti-inflammatory capacity, which offered a paradigm to wound treatment for valuable therapeutic advantages (Fig. 8d).

Fig. 8.

(a) Schematic representation of Cu-PTA NPs for promoting infected wound repair. (b) Schematic diagram of the preparation of GNRs@MPNs and its anti-infective treatment in vivo. (c) Schematic representation of the synthesis of Kaol@GOx@Fe-TA and its synergistic multiple therapeutic effects on wound healing, including hemostatic, bactericidal, and anti-inflammatory effects. (d) In vivo therapeutic effect evaluation of Kaol@GOx@Fe-TA

It is worth noting that MPNs-containing hydrogel dressings are widely applied to wound repair, in which MPNs serves as the active ingredient or the cross-linked skeleton of hydrogels [122–125]. The elevated oxidative stress and inflammatory reaction after skin damage remained a huge challenge, which could aggravate the wound microenvironment and impair the success of wound repair. Considering the excellent scavenging of ROS and anti-inflammatory capacity of MPNs, Ye et al. designed EGCG-Ce complex loaded antibacterial hydrogel dressing (E@C Gel) for skin repair and regeneration (Fig. 9a) [126]. In this study, EGCG-Ce had excellent antioxidant ability towards kinds of ROS via SOD-like or CAT-mimicking catalytic activity, which could promote M2 macrophages polarization and reduce the pro-inflammatory cytokines secretion. In vivo skin wound repair experiment confirmed E@C Gel could effectively enhance the wound repair and epidermis regeneration with a mature dermis layer, which was better than the treatment of EGCG-Ce or hydrogel alone (Fig. 9b). In addition, the EGCG-Cu capsule was directly loaded into a hydrogel wound dressing (SilMA/HAMA/Cu-EGCG) to promote the infected wound healing [127]. The SilMA/HAMA/Cu-EGCG hydrogel could enhance angiogenesis and suppress inflammation though continuous release of copper ions and EGCG, as well as inhibit Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The full-thickness infected wound repair in vivo demonstrated that this hydrogel dressing could notably accelerate wound repair though promote collagen deposition and angiogenesis. This study exhibited a broad potential of controlled-release antibacterial hydrogel for chronic wound healing. Hu and co-workers constructed a novel tea polyphenol (TP) self-assembled magnesium (TP-Mg) nanoparticles for the first time, and introduced them into double network hydrogel through swelling performance in order to avoid complicated chemical crosslinks [128]. The TP-Mg could degrade and release from the hydrogel under the acidic microenvironment to inhibit MRSA biofilm, which could significantly enhance diabetic foot wound repair. Curcumin (Cur) has been widely used in the biomedical field because of its excellent anti-inflammatory and antioxidant properties, but its poor water solubility and poor bioavailability limit its clinical application. Curcumin-metal networks can improve its availability and have been successfully applied to wound repair [129, 130]. Shen et al. designed a nanocomposite hydrogel dressing with low-level laser therapy, shaped moldable, adhesive, and self-healing performance consisting of oxidized hyaluronic acid (OHA), ε-poly-L-lysine grafted human-like collagen (HLC-EPL), and curcumin-Fe nanaoparticles for burn wounds therapy (Fig. 9c) [55]. This nanocomposite hydrogel (Cur-Fe Fe³⁺-HEO) could release cur under the acidic environment of the wounds in the inflammatory stage owing to the coordination structure of Cur-Fe. Additionally, Cur- Fe³⁺-HEO hydrogel had the self-monitoring drug release and distribution capacity due to the adjusted autofluorescence state of whether the Cur was coordinated with Fe ions or not. The animal experiments in vivo confirmed that the composite hydrogel could greatly shorten the wound closure from 21 days to 9 days though decreasing the inflammatory factors levels, enhancing angiogenesis, and promoting collagen formation and deposition (Fig. 9d). Subsequently, the Cur-magnesium polyphenol network was introduced to the antibacterial hydrogel composed of ε-poly-L-lysine (ε-PLL)/polymer poly(γ-glutamic acid) (γ-PGA) to enhance burn wound repair [131]. The composite dressing (Cur-Mg@PP) could rapidly absorb wound exudate, resulting in a powder-to hydrogel-transition due to the high water absorption performance of ε-PLL and γ-PGA. The released Cur and Mg²⁺ from the composite hydrogel exhibited excellent analgesic, antibacterial, anti-inflammation, antioxidant, and vascularization, which could prominently improve burn wound repair. MPNs could also be used as a cross-linking network for hydrogels, taking advantage of them unique properties for tissue repair applications [123, 132]. A series of naturally-derived polyphenols consisting of TA, oligomeric proanthocyanidins (OPC), and EGCG was applied to synthesized copper crosslinked nanoparticles (Cu NPs) via the coordination between Cu²⁺ and polyphenols by Wei and co-workers [132]. The various Cu NPs were then incorporated into the hydrogel network consisting of polyphenols and phenylboronic acid (PBA)-grafted carboxymethyl chitosan (CMCS). These hydrogels showed porous structure and excellent self-healing capacity owing to the dynamic boronate ester bonds and Schiff base. At the same time, these hydrogels also had excellent hemostatic behavior and outstanding antibacterial capacity during the synergistic effect of CMCS, polyphenols and Cu²⁺. In vivo full-thickness mice skin defect experiments suggested that these hydrogels could significantly enhance wound repair through facilitating granulation tissue generation, M2 macrophage polarization, and collagen deposition. The current treatment of diabetic wounds is not particularly ideal. Fu et al. designed a TA-europium coordination components crosslinked citrate-containing mussel-prompted bioadhesives (TE-CMBAs) for the convenient treatment of diabetic wounds thanks to multiple interactions of TA with metal ions and polymers (Fig. 10a) [133]. TE-CMBAs had a short gelation time (< 60 s), good shape adaptation, appreciable mechanical strength, and excellent wet tissue adhesion (≈ 40 kPa). TE-CMBAs showed self-healing, pH-responsive europium ion and TA release properties due to reversible hydrogen bond cross-linking and sensitive metal-phenol coordination. Notably, TE-CMBAs possessed on-demand removability when mixed with borax solution, alleviating the hassle of dressing changes and eliminating secondary damage caused by traumatic dressing changes. The results in vitro demonstrated that TE-CMBAs showed outstanding photothermal antibacterial, antioxidant, and anti-inflammatory capacity. The diabetic chronic wound model was applied to evaluate the wound repair efficacy of TE-CMBAs. The data confirmed that TE-CMBAs provided a promising therapeutic strategy for diabetic wound because of promoting the transition from inflammatory to proliferation phase, and enhancing re- epithelialization as well as tissue remodeling (Fig. 10b). Due to the excellent adhesiveness of MPNs, it has been proved that MPN can be coated on the surfaces of different substrates. Inspired by this, Zhou et al. designed Gel/L@FeTA hydrogels using layer-by-layer self-assembly [134]. In this study, the tannic acid and ferric ions was assembled on the surface of the L. reuteri to prevent antibiotic interference. Then, the shield probiotics were introduced into an injectable hydrogel (Gel/L@FeTA). Gel/L@FeTA contributed to the survival of probiotics and supported the continuous secretion of lactate for biological activity in an environment including gentamicin. In addition, Wu et al. designed a novel composite system: probiotics were encapsulated in MPNs crosslinked by proanthocyanidins and Ca²⁺, and then incorporated into konjac glucomannan/xanthan gum (KGM/XG)-based hydrogels for infected wound healing (Fig. 10c) [135]. The MPNs could not only inhibit the leakage of probiotics, but also resist the interference of antibiotics on strain activity. The results of animal experiments showed that the healing rate of infected wounds was as high as 98.31% on the 14th day after treatment with KGXM-PCB@B. subtilis hydrogel (Fig. 10d), which confirmed that the system could significantly accelerate the repair process of infected wounds.

Fig. 9.

(a) Schematic representation of the E@C gel hydrogel dressing for ROS scavenging and immunomodulatory wound treatment. (b) E@C gel hydrogel dressing promoted healing and tissue regeneration evaluation of full-thickness skin wounds in vivo. *P < 0.05, **P < 0.01, ***P < 0.001. (c) Schematic diagram of preparation of Cur-Fe(III)-HEO nanocomposite hydrogel and its treatment of burn wounds. (d) In vivo evaluation of drug release and efficacy in promoting wound healing

Fig. 10.

(a) Schematic illustration of preparation of tannin-europium coordination complex (TEC) cross-linked citrate-based mussels bioadhesives (TE-CMBAs) and accelerated diabetic wound healing. (b) Evaluation of diabetic wound healing in vivo. (c) Diagram of KGXM-PCB@Bsubtilis hydrogel synthesis and promoting infected wound healing. (d) In vivo effects of the S. aureus-infected full-thickness skin treatment

Bone and cartilage repair

MPNs combines the specific functionality of metal ions and polyphenol ligands, showing unique advantages specifically designed to meet the desired properties of orthopedic biomaterials [16, 136–138]. EGCG is a naturally occurring polyphenol found in abundance in green tea and has been scientifically proven to possess remarkable properties containing scavenging of ROS, strong antioxidant effects and anti-inflammatory behavior [139]. Therefore, EGCG has potential applications in improving the pathological microenvironment of bone defects. In addition, EGCG has the ability to bring about complementary functions through the formation of metal-polyphenol networks by cooperating with various metal ions. It has been found that Mg²⁺ is an essential ion in bone repair, with low toxicity and the capacity to stimulate osteoblast differentiation via the Wnt/β‑catenin and ERK signaling pathways [140, 141]. Based these advantages, Lee et al. designed a titanium (Ti) alloy coated with EGCG-Mg networks for promote osseointegration [142]. The results in vitro and in vivo both demonstrated that EGCG-Mg coated Ti could enhance osteogenic differentiation in human adipose-derived stem cells (hADSCs) during the cooperative interaction of EGCG and Mg²⁺. Strontium (Sr) is an alkaline earth metal that has been found to promote osteoblast differentiation and bone formation, as well as inhibit osteoclast activity and reduce bone resorption. The application of Sr- polyphenol complexes might have the huge potential to promote osteoblast. Liu et al. introduced polydopamine -coated EGCG-Sr complexes (PMPNs) into scaffolds based on extracellular matrix (ECM) and ultra-long nanowires of hydroxyapatite (nHAWs) for bone regeneration (Fig. 11a) [143]. The PMPNs@ECM/nHAW scaffold had good biocompatibility, and could scavenge free radical and ROS, promote cell migration and pro-angiogenesis, and ultimately induce osteogenic differentiation of stem cells. Upon incorporation of PMPNs, the Young’s modulus of the PMPNs@ECM/nHAW scaffold was significantly increased to 0.293 ± 0.082 MPa, which is approximately 292% higher than that of the ECM scaffold, enabling better adaptation to bone tissue. In addition, the PMPNs@ECM/nHAW scaffold also exhibited good photothermal properties due to the presence of PMPNs. In vivo rat cranial defects model confirmed that the PMPNs@ECM/nHAW scaffold and near-infrared (NIR) light could synergistically improve the bone regeneration (Fig. 11b). Inspired by clinical bone cement filling therapy, Hu et al. composited α-c phosphate (α-TCP) with self-curing behaviors with β-tricalcium phosphate (β-TCP) and developed biomimetic a cancellous bone scaffold system α/β-tricalcium phosphate (α/β-TCP) by 3D printing in low temperature [144]. The gelatin in this scaffold preserved as an organic phase, which was then loaded with a tea polyphenol magnesium (TP-Mg) nanoparticle (Fig. 11c). The α/β-TCP@TP-Mg composite scaffold exhibited antibacterial, anti-inflammatory, and osteoinductive performance after loading TP-Mg nanoparticles. It also showed an excellent repair effect in infectious bone defects model in vivo through regulating the early complex microenviornment. In the 12th week, there were thicker and more new bone tissue in the 30α/β-TCP@10TP-Mg group compared with other groups. This study provided a meaningful approach for the exploration of the treatment of infected bone defects accurately without the need for secondary surgery or overuse of antibiotics. In addition, Zheng et al. developed a cryogel scaffold functionalized with magnesium-based nanoparticles (TMgP) for bone defect repair [145]. Mechanical characterization revealed that the incorporation of TMgP increased the compressive modulus of the cryogel by 1.5-fold, thereby providing enhanced mechanical support for bone regeneration. The scaffold exhibited excellent biocompatibility, and supported the adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs). TMgP-modified cryogels effectively induced macrophage polarization toward the M2 anti-inflammatory phenotype, downregulated pro-inflammatory cytokines (TNF-α, IL-6), and upregulated anti-inflammatory cytokines (IL-10, TGF-β), thereby establishing a favorable microenvironment for tissue regeneration. Furthermore, the scaffold promoted osteogenic differentiation of BMSCs through the release of bioactive ions, as evidenced by increased alkaline phosphatase (ALP) activity, enhanced mineralization, and upregulation of osteogenic genes (Runx2, OCN, OPN). In vivo studies further confirmed that the cryogels significantly promoted new bone formation in critical-sized calvarial defects by coordinating immunomodulatory, osteogenic, and angiogenic responses. MPNs assembled from polyphenols and metal ions had good advantages in the surface functionalization of materials due to their simple preparation process and wide adaptability. Polymer scaffolds could be easily modified with MPNs to enhance ROS scavenging and used metal ions to build bone integration, thereby improving the efficiency of bone tissue regeneration [146, 147]. The bottleneck in diabetic bone defects is centered on the multifunctional need for implants to remodel the hyperglycemic microenvironment and repair compressed bone remodeling. In clinical practice, polyether ether ketone (PEEK) and titanium (Ti) are commonly used to treat diabetic weight-bearing bone defects [148, 149]. However, their poor bioactivity and antimicrobial activity, inability to regulate local hyperglycemia, leading to high implant loosening rate and even surgical failure are the drawbacks that hinder their clinical application in diabetic bone implants. Based on these issues, He et al. designed a glucose-primed orthopedic implant consisting of PEEK, glucose oxidase (GOx), and Cu-based MPNs as the functional coating for enhancing diabetic osseointegration [150]. After introducing Cu-based MPNs, the water contact angle was sharply decreased to 35.33 ± 2.47°. In a diabetic infection microenvironment, GOx on the implant consumed glucose to generate H₂O₂, and Cu released from the coating could catalyze the generation of H₂O₂ to produce highly bactericidal •OH, which could kill the pathogenic bacteria through light-enhanced chemodynamic therapy. The implant showed excellent osteogenicity owing to the existence of Cu and polydopamine coating as evidenced by the upregulated expression of osteogenesis-related genes, including ALP, OCN, and Runx2. In an infected diabetic rat model of bone defects, the modified PEEK significantly enhanced the osteogenic differentiation of BMSCs and promoted calcium nodule formation. This osteogenic effect correlated with the downregulation of the MAPK, IL-17, TNF, and NF-κB pathways in M1 macrophages, as well as the upregulation of oxidative stress-related pathways, including peroxisome and glutathione metabolism, thereby combatting ROS and supporting bone regeneration.

Fig. 11.

(a) Schematic diagram of the synthesis of PMPNs@ECM/nHAW biomimetic scaffold and promoting bone regeneration. (b) In vivo bone formation evaluated by photothermal therapy with PMPNs@ECM/nHAW scaffolds. (c) Schematic illustration of a self-developed bioactive bone repair scaffold incorporating TP-Mg for infected bone defect therapy. (d) Evaluation of therapeutic efficacy of skull defect repair in vivo

In addition, surface functionalization strategies of MPNs have also been used to restore oxidative homeostasis and promote osseointegration. Zhang et al. used catechols and Zn²⁺ and Ni²⁺ metal ions to modify a range of polymer scaffolds, including polybutylene succinate (PBS), polylactide (PLA), polycaprolactone (PCL), and PEEK [151]. The fabricated polymer scaffolds showed good biocompatibility, great intracellular ROS removing capacity, which could effectively improve therapeutic efficacy in mouse skull model in vivo (Fig. 11d). These surface functionalization approach could significantly promote the complex physiological microenvironment in the bone defect site and enhance the efficiency of bone tissue repair. Furthermore, osteochondral defects cannot be effectively repaired owing to their special physical structure and pathological microenvironment such as oxidative stress and inflammation. Cao et al. developed a novel silk-based hydrogel incorporated with Cu-containing MPNs (CuTA@SF) to promote the microenvironment for improving osteochondral regeneration (Fig. 12a) [152]. The introduction of CuTA nanozymes gave the SF hydrogels a uniform microstructure and high hydrophilicity. The water contact angles of CuTA@SF and TA@SF were 5° and 18°, respectively, which are lower than those of SF (40°) and Cu@SF (27°). CuTA@SF hydrogel could accelerate the proliferation of mesenchymal stem cells (MSCs) and chondrocytes and enhances cell viability, while possessing antioxidant and antimicrobial properties. Under the IL-1β-stimulated inflammatory environment, CuTA@SF hydrogel still had the potential to enhance MSCs osteogenesis and cartilage-specific extracellular matrix (ECM) deposition. Subsequently, proteomics analysis was further suggested that CuTA@SF hydrogel increased the expression of osteogenesis-related pathway proteins, affected apoptosis signaling pathway, and promoted cell proliferation. In a rabbit whole-layer osteochondral defects model finally confirmed that CuTA@SF hydrogel could successfully promote in situ osteochondral regeneration (Fig. 12b). In addition, MPNs have also been employed to modify coaxial electrospun biomembranes for the multifaceted regulation of the bone defect microenvironment. Zheng et al. fabricated a core–shell structured biomembrane via coaxial electrospinning using polylactic acid (PLA) as the substrate, with chitosan incorporated into the shell layer and simvastatin encapsulated within the core layer [153]. The membrane surface was further modified with a TA-Fe³⁺ coating (denoted as PCS@MPN). The results demonstrated that MPNs modification significantly enhanced the tensile strength of the electrospun membrane, rendering its mechanical properties more suitable for bone defect repair. Furthermore, the coating endowed the membrane with excellent photothermal responsiveness, enabling near-infrared (NIR) light-triggered on-demand release of simvastatin. Notably, the combination of PCS@MPN10 and NIR irradiation (PCS@MPN10 + NIR) markedly alleviated intracellular oxidative stress, scavenged mitochondrial reactive oxygen species (mtROS), and restored mitochondrial function via activation of the PI3K-Akt signaling pathway, thereby effectively promoting osteogenic differentiation. Additionally, the membrane exhibited favorable antibacterial activity and the capacity to modulate macrophage polarization from the M1 to the M2 phenotype, further optimizing the regenerative microenvironment. This study provided a promising strategy for bone repair by integrating MPNs coating-mediated mechanical reinforcement, photothermal-responsive drug release, and synergistic antioxidant–mitochondrial protective effects.

Fig. 12.

(a) Schematic diagram of CuTA@SF hydrogel synthesis and the mechanism for promoting cartilage repair. (b) Evaluation of CuTA@SF hydrogel for cartilage repair in vivo

Osteoarthritis and rheumatoid arthritis repair

Osteoarthritis (OA) is a chronic disease caused by inflammation of the joints and is one of the mo mmon chronic musculoskeletal diseases [154]. Due to the antioxidant and anti-inflammatory properties of polyphenols and the unique properties of metal ions, MPNs were also able to promote effectively repair of osteoarthritis. Chen et al. designed a nanofiber microspheres (TSMS) modified by MPNs consisting of TA and Sr²⁺ for effective osteoarthritis therapy (Fig. 13a) [155]. The TSMS showed porous structure, which could sustainably release TA. In addition, the TSMS showed excellent antioxidant and anti-inflammatory properties, as well as higher cell viability and cartilage-associated extracellular matrix (ECM) secretion. In a rabbit model of papain-induced OA, TSMS also suppressed cartilage degradation and significant repair effects, and the inhibited expression levels of inflammatory factors, such as tumor necrosis factor- α (TNF- α) and interleukin-1- β (IL-1 β). These results confirmed that TSMS could effectively enhance OA regeneration. However, the dense extracellular matrix and avascularity of articular cartilage hamper the effective penetration of injected drugs, thereby limiting their therapeutic efficacy [156]. WYRGRL peptide, as a new type of peptide, is specially designed to bind to type II collagen in cartilage matrix with high specificity and achieve accurate recognition and targeting of chondrocytes [157]. Based on this property, Zhao et al. developed a multifunctional bioengineered heterojunction material (MBM-HW) with a structure composed of a two-dimensional Mo₄/₃B₂₋ₓ MBene combined with CeGA MPN [158]. Then it was coated with a cartilagon-targeted shell of hyaluronic acid and WYRGRL peptide by self-polymerization at the interface for the treatment of OA. MBM-HW not only mimic the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) to efficiently remove excessive ROS, but also had dual response and release ability and cartilage targeting function. Both in vivo and in vitro experiments, MBM-HW was shown to effectively alleviate oxidative stress, preserve mitochondrial function, and inhibit cartilage matrix degradation in chondrocytes, thereby mitigating osteoarthritis (OA) progression. Mechanistically, these effects were mediated through suppression of the Perk/eIF2α signaling pathway, which attenuated ferroptosis and maintained cartilage homeostasis, highlighting targeting of this integrated stress response as a novel therapeutic approach for OA.

Fig. 13.

(a) Schematic diagram of the synthesis of microspheres modified by TA/Sr²⁺ and OA treatment. (b) Schematic diagram of m-ec fabrication and therapeutic mechanism in rheumatoid arthritis. (c) Schematic illustration of the ultrasmall iron-quercetin metal-natural product nanocomplex with dual antioxidant and macrophage-regulatory activities for rheumatoid arthritis therapy. (d) Rheumatoid arthritis treatment using iron-quercetin nanocomplex in vivo

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that has been shown to be associated with inflammatory cells infiltrating the synovium and causing severe destruction of articular cartilage [159]. Considering the excellent ROS scavenging ability of MPNs, Song et al. constructed a macrophage membrane-encapsulated EGCG-Ce nanoparticle (M-EC) for achieving RA repair (Fig. 13b) [160]. Because the geometrical structure of EC was similar with the active metal sites of natural antioxidant enzymes, EC has a robust scavenging efficiency for various of ROS and reactive nitrogen species (RNS). Macrophage cell membranes help M-EC to escape from the immune system, which could be taken up by inflammatory cells, and exceptionally bind IL-1β. In a collagen-induced arthritis model, M-EC could accumulate at inflammatory joints, and promote RA repairing though alleviating synovial inflammation, inversing the phenotype of macrophages, and decreasing cartilage erosion. In addition, iron-quercetin (Fe-Qur) natural coordination nanoparticles have also been used to treat RA due to their excellent anti-inflammatory and antioxidant properties (Fig. 13c) [161]. Fe-Qur has better water solubility and biocompatibility, while retaining quercetin’s inherent ability to remove ROS. Fe-Qur could effectively eliminate excess ROS, prevent cell apoptosis and suppress the polarization of inflammatory macrophages via alleviating the activation of NF-κB pathway. The in vivo experiments on RA model demonstrated that Fe-Qur significantly reduced joint swelling, showing the excellent therapeutic effect (Fig. 13d). This was because that Fe-Qur markedly reduced inflammatory cell infiltration and increased anti-inflammatory macrophage phenotype, thereby inhibiting osteoclasts and leading to bone erosion. These researches suggested that MPNs had a huge potential to treat RA and other inflammation-related diseases.

Cardiac tissue regeneration

Ischemic heart disease (IHD) is one of the most common cardiovascular diseases and poses a significant health burden worldwide [162, 163]. During the time course of ischemia development, cardiac muscle cells are severely damaged. However, rapid reperfusion of blood flow may inevitably lead to a burst of ROS generation, and toxic ROS can damage cell membranes through lipid peroxidation, denaturing enzymes, and cleavage of DNA strands, ultimately inducing cardiomyocyte death through programmable pathways [164]. Hence, there is an urgent need to develop drugs with dual anti-inflammatory and free radical scavenging effects to mitigate cardiac damage. Currently, targeted drug delivery in the fluid circulation has emerged as a promising area for the treatment of myocardial infarction, and TA has been reported to have cardiac-targeted effects [165]. Therefore, Liu et al. utilized the strong coordination between Fe³⁺ and curcumin (Cur), an anti-inflammatory drug, to synthesize a novel drug-based nanoenzyme, Fe-Cur@TA, which was further modified with TA for targeted treatment of myocardial infarction (Fig. 14a) [166]. The results confirmed that Fe-Cur had strong anti-inflammation and free radical scavenging behaviors, which could effectively decrease acute immune cells aggregation, induced M2 macrophage polarization, and reduced inflammatory cytokine secretion. It’s worth noting that the accumulation of Fe-Cur@TA in cardiac tissue was ten times higher than that of Fe-Cur due to the high affinity of TA for cardiac elastin and collagen. In mouse and preclinical beagle myocardial infarction models, Fe-Cur@TA could preserve cardiac function and relieved adverse heart remodeling, suggesting promising clinical applications in cardiovascular disease. Subsequently, Tang et al. modified cellulose acetate cigarette filter with TA chelating Cu²⁺ (TA-Cu) complex to prepare functional Cig /(TA-Cu) heart patch for myocardial infarction repair (Fig. 14b) [167]. Cig /(TA-Cu) patches basically preserved the anisotropic microstructure of the filter material similar to that of natural cardiomyocytes, and improved the electrical conductivity due to the introduction of TA-Cu complexes, which could promote the elongation, orientation and maturation of cardiomyocytes. In addition, Cig /(TA-Cu) could effectively remove ROS, reduce cardiomyocyte apoptosis, promote endothelial cell vascular regeneration, and ultimately promote myocardial electrical integration, thus improving cardiac function. In addition, Wang et al. found that TA-Ce organo-metal complexes had good cardiomyocyte targeting ability and could effectively scavenge oxidizing substances such as hydrogen peroxide, superoxide anion, and hydroxyl radicals, thus effectively preventing cardiomyocyte death (Fig. 14c) [168]. Mechanistically, TA-Ce was found to modulate key KEGG pathways associated with apoptosis, such as the MAPK, NF-κB, PI3K-Akt, and TNF signaling pathways. In vivo imaging suggested that the TA-Ce could specifically target the cardiac and accumulate for up to 6 h. Furthermore, in a mouse myocardial ischemia/reperfusion injury model, TA-Ce effectively improved cardiac function, reduced myocardial infarction area, and greatly attenuated cardiac apoptosis (Fig. 14d). This study demonstrated that the MPNs possessed great therapeutic promise in ischemic heart diseases.

Fig. 14.

(a) Schematic illustration of the synthesis of the Fe-Cur@TA nanozyme and its mechanism for treating myocardial infarction via cardiac-targeted disruption of the vicious cycle between excessive inflammation and free radicals. (b) Schematic illustration depicting the preparation process of CP from cigarette filters and its role in promoting repair of the infarcted heart. (c) Schematic illustration of the synthesis of cardiomyocyte-targeting TA − Ce nanocatalysts and their mechanism for treating myocardial ischemia/reperfusion injury by scavenging ROS and protecting myocardial function. (d) In vivo evaluation of TA − Ce NCs for alleviating myocardial ischemia/reperfusion (IR) injury

Spinal cord injury repair and alzheimer’s disease therapy

Spinal cord injury (SCI) could lead to severe motor impairment or even complete leg paralysis [169]. Studies have reported that activated macrophages and neutrophils could accumulate in the injury site, leading to a significant increase of ROS after spinal cord injury [170, 171]. Due to the excessive production of ROS in SCI, lipids, proteins and DNA are severely oxidized and damaged, which lead to increased inflammation and neuronal cell death. By regulating ROS balance through using antioxidants, it promotes recovery and significantly improves patient status by facilitating nerve regeneration and functional recovery after SCI [172]. Since polyphenols have excellent ROS scavenging ability, Chen et al. synthesized PA-Zn nanoenzymes using the coordination of pyrogallol (PA) and zinc, which could mimic SOD and CAT enzyme activities for the treatment of SCI (Fig. 15a) [173]. In this study, PA-Zn effectively inhibited the expression of ROS and M1 macrophage-associated markers (IL-1β) and up-regulated the expression of M2 macrophage-associated markers (Arg-1). In addition, PA-Zn markedly promoted the survival of ventral horn neurons in vivo, while inhibiting spinal cord injury and reducing macrophage infiltration at the lesion site (Fig. 15b). At a very low dose and a shorter time, PA-Zn showed a better therapeutic effect on spinal cord injured animals. This study demonstrated that metal-polyphenol nanoenzymes had a promising potential clinic merit for SCI and other neuroinflammation-related diseased. In addition, an intelligent controlled drug delivery system based on the modular design of “egg” nanoparticles has been used for the repair of SCI [174]. The “egg” nanoparticles consisted of a three-layer structure: tannic acid/Fe³⁺/tetradecanol “eggshell”, zeolitic imidazolate framework-8 (ZIF-8) “protein” and paclitaxel “yolk”. The “egg” nanoparticles cleverly achieve controlled drug release by inducing signaling cascades in response to external and internal stimuli. This strategy achieved precise spatiotemporal drug release, promoted endogenous neural stem/progenitor cells and differentiation in vitro, and facilitated nerve regeneration, synapse formation and axonal remyelination in vivo.

Fig. 15.

(a) Schematic diagram depicting the preparation of PA-Zn nanozymes and their mechanism in spinal cord injury therapy. (b) PA-Zn/Gel enhances functional recovery after spinal cord injury. (c) Schematic illustration of the construction of K8@Fe–Rh/Pda nanoparticles and their therapeutic mechanism for Alzheimer‘s disease. (d) Neuroprotective effects and cognitive improvement of K8@Fe − Rh/Pda nanoparticles in APP/PS1 mice

Alzheimer’s disease (AD) is a global neurodegenerative disorder and the leading cause of dementia in the elderly [175, 176]. The presence of amyloid fibril plaques in brain tissue is a core pathological feature of the disease and plays a critical role in its progression. Zhang et al. evaluated the effects of various MPN-coated gold nanoparticles on the formation of amyloid fibrils associated with AD [177]. The results demonstrated that all tested particles could effectively inhibit fibril formation. Among them, the particles coated with cobalt (II) MPN exhibited the most significant inhibitory activity, reaching up to 90%. Currently, the treatment strategies for AD mainly focus on inhibiting the abnormal aggregation of abnormal amyloid beta (Aβ) peptide. However, these drugs mainly aim to alleviate the aggregation phenomenon of Aβ, but usually lack the ability to repair the resulting neuronal damage. Due to the excellent antioxidant properties of the MPNs, Yin et al. developed a stepwise coordination method to rationally design a complex nanoparticle drug (Fe − Rh/Pda NPs) for enhancing the therapeutic effect on AD (Fig. 15c) [178]. To enable it to cross the blood-brain barrier (BBB) and target (Aβ), the KLVFFAED (K8) peptide was covalently modified onto the surface of nanoparticles, resulting in K8@Fe − Rh/Pda NPs. This nanosystem could efficiently deliver rhein to the brain, promoting mitochondrial biosynthesis by upregulating the SIRT1/PGC-1α pathway, thereby alleviating oxidative stress and exerting neuroprotective effects. Moreover, in the APP/PS1 mice model, K8@Fe − Rh/Pda NPs successfully reversed neural damage and cognitive decline without any toxicity, demonstrating outstanding therapeutic potential (Fig. 15d).

Other tissue repair

Periodontitis is an infectious chronic inflammatory disease, which is often caused by poor oral hygiene (such as incomplete tooth cleaning) and lifestyle factors such as long-term high-sugar diet [179]. The disease not only manifests as local symptoms such as gingival swelling and bleeding, but also causes progressive absorption and loss of alveolar bone. In severe cases, it may even lead to tooth loosening and loss, which in turn affects basic oral functions such as chewing and pronunciation. Studies have shown that excessive oxidative stress disrupts the balance between ROS and antioxidant defense, which is one of the important mechanisms of the occurrence and development of periodontitis [180]. MPNs have shown great potential in the intervention of periodontitis due to their excellent antioxidant and anti-inflammatory properties. In addition, MPNs also possess good bioadhesive properties and can be retained in a moist oral environment for a long time, thereby significantly prolonging the action time and enhancing the therapeutic effect.

Proanthocyanidins (PCs) are flavonoid compounds commonly found in natural products, exhibiting potent pharmacological effects, such as anti-inflammatory, antioxidant, anti-tumour, and cardiovascular protective properties [181]. MPNs has the unique advantages of simple synthesis and good affinity with human tissues, making it suitable as a natural coating to cover other materials. Fe³⁺ and polyphenols can form stable MPNs films on the substrate surface, where the antioxidant performance is superior to that of the corresponding free phenolic compounds [182]. Meanwhile, the network structure formed by iron and polyphenols has efficient photothermal properties. Based on this, Wang et al. designed a new type of photothermal nanocomposite, and coated MPNs on the surface of branched AuAg nanoparticles (named as AuAg@PC-Fe) to achieve the combined effect of photothermal antibacterial treatment and immunotherapy (Fig. 16a) [183]. The proanthocyanidin (PC)-Fe network enhanced the photothermal performance of AuAg nanoparticles, enabling effective antibacterial activity against periodontal pathogens through photothermal therapy. Moreover, it relieved oxidative stress and suppressed excessive inflammation. The therapeutic mechanism of AuAg@PC-Fe involved promoting M2 macrophage polarization through activation of the PI3K/Akt signaling pathway, thereby regulating tissue regeneration to repair periodontal damage. Additionally, it upregulated Nrf2 to scavenge ROS and subsequently inhibited the NF-κB signaling pathway to control inflammation. In vivo studies in mouse models demonstrated that AuAg@PC-Fe combined with near-infrared (NIR) irradiation exhibited superior therapeutic efficacy against periodontitis and significantly enhanced collagen fiber formation. To enhance the utilization rate of metal polyphenols, Xu et al. loaded tannic acid-copper (TA-Cu) coordination nanosheets into a viscous injectable hydrogel (TM/BHT), forming a multifunctional composite material [184]. This composite hydrogel possesses antibacterial, antioxidant, anti-inflammatory and osteogenic properties, and shows potential application value in the treatment of periodontitis. It has enhanced local retention ability at the lesion site, thereby reducing the frequency of metal polyphenol administration. Due to the introduction of ester bonds that can be hydrolyzed by enzymes in the hydrogel network, the controlled and on-demand release of CuTA was achieved. Moreover, CuTA can simulate the activities of superoxide dismutase (SOD) and catalase (CAT), effectively alleviating oxidative stress, and by regulating the Nrf2/NF-κB signaling pathway, inhibiting the expression of pro-inflammatory factors and upregulating osteogenic-related genes, further promoting periodontal tissue regeneration (Fig. 16b). Subsequently, Ouyang et al. prepared Ca²⁺ -tannic acid nanocomposites loaded onto injectable sodium alginate/four-arm polyethylene glycol-lipoic acid hydrogel (CaTA@Gel) for periodontitis treatment [185]. The composite hydrogel not only had good mechanical properties, but also could continuously release CaTA nanocomposites, thereby inhibiting bacteria, scavenging ROS, and promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through Ca²⁺.

Fig. 16.

(a) Schematic illustration of the synthesis of AuAg@PC-Fe andits antibacterial, antioxidant, and anti-inflammatory functions in periodontitis therapy. (b) Therapeutic efficacy of TM/BHT/CuTA against periodontitis. (c) The schematic diagram of the synthesis process of ZGNFs and its advantages in treating Gram-positive bacterial keratitis. (d) Schematic diagram depicting the synthesis of EGCG-Zn nanoparticles and their mechanism in combating oxidative stress-induced damage (lysosomal, mitochondrial, and DNA) in lens epithelial cells to prevent cataract formation

Bacterial keratitis is inflammation, necrosis and ulceration of the cornea caused by bacterial infection [186]. It can lead to severe visual impairment and even blindness if not treated timely. Metal ions have good bactericidal effects due to their ability to bind proteins and nucleic acids. However, in the physiological environment, free metal ions can inactivate proteins and cells, thus limiting their application in bactericidal activities in vivo. Polyphenols are rich in hydroxyl groups, which can stabilize metal ions and achieve controlled release in a specific environment. Huang et al. achieved the treatment of MRSA-induced bacterial keratitis by constructing gallic acid-Zn nanoflowers (ZGNFs) in a simple hydrothermal approach (Fig. 16c) [187]. ZGNFs can specifically adhere to Gram-positive bacteria and release Zn²⁺ in acidic infection environment, showing good bactericidal effect. In vivo experiments showed that ZGNFs had self-targeting properties and could be well retained at the infection site to effectively eliminate MRSA, thereby promoting the treatment of keratitis. Subsequently, Li et al. introduced poly-L-lysine into the gallic acid-Zn system, constructed gallic acid-Zn-poly-L-lysine composite nanomaterials (ZGNC) through a self-assembly strategy, and applied it to the treatment of bacterial keratitis [188]. Due to the positive charge on the surface of ZGNC, ZGNC could be effectively adsorbed on the bacterial cell membrane through electrostatic interaction, thereby achieving efficient killing of Gram-positive and Gram-negative bacteria, which was demonstrated in a bacterial keratitis model in vivo. Tobramycin (TOB) is an antibiotic commonly used to treat infections such as bacterial keratitis. However, the efficacy of free TOB eye drops in the treatment of refractory corneal ulcers is limited due to its short retention time and poor permeability to the corneal physiological barrier and bacterial biofilm. To address this problem, Gao et al. loaded TOB into a network composed of 3,4, 5-trihydroxybenzaldehyde (THBA), -poly-ʟ -lysine (EPL), and Cu²⁺ to form THBA-Cu-TOB nanoparticles through metal-phenol coordination and Schiff base reaction [189]. The resulting THBA-Cu-TOB nanoparticles significantly enhanced drug penetration and were effective to eradicate P. aeruginosa biofilms at a low dose of TOB (2.6 µg·mL⁻¹). In the keratitis ulcer model, THBA-Cu-TOB nanoparticles could not only effectively eliminate ROS and reduce inflammation, but also promote the migration of corneal epithelial cells, ultimately achieving efficient repair of refractory corneal ulcers. Mechanistically, treatment with THBA-Cu-TOB significantly downregulated the Toll-like receptor 4 and NF-κB signaling pathways, leading to reduced secretion of inflammatory cytokines.

Cataract represents another common eye disease, characterized by lens opacification or discoloration that degrades optical quality [190]. In contrast to acute bacterial keratitis, it is typically a slow-progressing degenerative condition. During the occurrence and development of cataract, oxidative stress is a key pathogenic factor. It damages important biological macromolecules such as proteins, lipids and nucleic acids within the lens, disrupts the balance of the antioxidant defense system, induces lens opacity, and ultimately leads to the formation of cataract [191]. The MPNs demonstrate significant advantages in ocular drug delivery, such as strong structural stability, high cell uptake efficiency, and the ability to target multiple oxidative stress pathways. Wang et al. constructed EGCG-Zn nanoparticles based on the coordination effect between EGCG and zinc ions for cataract treatment (Fig. 16d) [192]. These nanoparticles exhibited good biocompatibility and could effectively scavenge free radicals, as well as reduced intracellular ROS level. Furthermore, the EGCG-Zn could significantly mitigate various ROS-induced cellular damages, including protecting lysosomal function, maintaining mitochondrial membrane potential, stabilizing the cytoskeleton, ensuing DNA synthesis integrity, and delaying cellular senescence. In the UV-B-induced cataract animal model, treatment with EGCG-Zn markedly reduced the degree of lens opacification, confirming its promising therapeutic potential for cataract prevention and treatment.

Biosafety

Biosafety represents a critical consideration in the field of nanomedicine. Although many nanomaterials, such as gold nanoparticles and graphene oxide, have demonstrated excellent drug delivery performance, their clinical translation has been hindered by concerns over potential long-term cytotoxicity [193]. MPNs are assembled from polyphenols and metal ions, with polyphenols being widely derived from plants and generally regarded as possessing favorable biocompatibility and safety [194]. Notably, the cytotoxicity of metal ions is a complex, multifactorial process that is not solely determined by acute toxicity. It is closely associated with metal ion release kinetics, local redox activity, coordination chemical stability, and dose thresholds. Specifically, the release rate of metal ions from MPNs dictates local transient concentrations. Excessive release may lead to sudden toxicity, while continuous release may cause chronic cellular damage. The biocompatibility of MPNs depends not only on the type of metal ion but also on the integrated regulation of ligand structure, coordination ratio, and microenvironmental conditions. It is important to note that the potential cytotoxicity of metal ions can be partially mitigated through chelation with polyphenols. For example, the acute and long-term biosafety of Cu²⁺-TA MPNs was assessed in a mouse model [195]. The results revealed high biocompatibility, as confirmed by body weight monitoring, H&E staining of major organs, and blood biochemical parameters. In addition, Björnmalm et al. further demonstrated that Ti⁴⁺ -tannic acid supramolecular gels maintained structural integrity for up to 14 weeks following subcutaneous administration, eliciting only mild foreign body reactions and exhibiting low titanium accumulation in distal tissues [196]. Nevertheless, systematic investigations into the long-term tissue distribution, organ retention, clearance pathways, and potential for chronic accumulation or delayed toxicity of MPNs remain lacking. In addition to metal ions, the degradation byproducts of polyphenolic ligands warrant careful consideration. Although many polyphenols possess intrinsic antioxidant and anti-inflammatory properties, their long-term biological effects following MPN degradation remain to be elucidated. Some studies suggest that phenolic compounds may undergo metabolic transformation or interact with endogenous biomolecules, potentially leading to unforeseen biological consequences [197]. This issue is particularly critical for nanomedicines that may require repeated administration or have potential for systemic exposure, as short-term low-toxicity data are insufficient to fully support safety conclusions. Therefore, more systematic and comprehensive safety evaluations are urgently needed to pave the way for their clinical translation.

Conclusions and perspective

MPNs, as an emerging class of biomimetic materials, are formed through the facile coordination-driven self-assembly of phenolic compounds and metal ions, attracting widespread attention due to their unique chemical properties and biomedical functions. This work systematically reviews the recent research progress in MPNs platforms, focusing on their core structural components, diverse synthesis strategies, multifunctional characteristics, and innovative applications in the field of tissue repair and regeneration. The review explains the construction basis of MPNs, which involves representative phenolic compounds with multivalent coordination ability (such as tannic acid, epigallocatechin gallate ester, etc.) and key biological functions of metal ions (such as Fe³⁺, Zn²⁺, Cu²⁺, etc.). It then details the primary synthesis strategies, including direct self-assembly, template-mediated self-assembly, and the sol-gel method. Thanks to their excellent adhesion, controllable degradability, and inherent multiple bioactivities such as antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, MPNs demonstrate significant application potential in tissue engineering. Finally, this review systematically summarizes the therapeutic effects of MPNs and their composite materials in various tissue repair models, covering skin wound healing, bone and cartilage regeneration, arthritis management, spinal cord repair, cardiac tissue engineering, and the treatment of periodontal and eye-related diseases. The challenges and future directions for the clinical translation of MPNs are also discussed. Although the MPNs has shown great potential for application in tissue engineering and regenerative medicine, it still faces a series of key challenges from basic research to clinical translation.

Currently, the advancement of MPNs is confronted with several critical challenges. (1) The structure-activity relationship remains inadequately elucidated. The intrinsic correlation between the microstructure of MPNs and their macroscopic functionalities has not been systematically established, thereby complicating the precise balance between their biological efficacy and potential toxicity. Consequently, this ambiguity impedes the determination of the optimal metal-to-phenolic ratio, ultimately restricting the full exploitation of material performance. (2) The synthesis of metal MPNs remains a complex and resource-intensive process. The preparation requires strict control over the stoichiometric ratio of metal ions to phenolic ligands and precise regulation of reaction conditions, resulting in a relatively high overall cost. Currently, the synthesis of the vast majority of MPN is still limited to small-scale laboratory settings, and significant challenges remain in achieving industrial-scale amplification. Hence, there is an urgent need to develop more efficient manufacturing processes that comply with Good Manufacturing Practice (GMP) standards, while also addressing issues related to terminal sterilization compatibility and long-term storage stability. This is a key prerequisite for the transition of MPN-based formulations from laboratory research to clinical application. (3) Biocompatibility is the key factor determining whether the MPNs can successfully be applied in the medical field. The metal ions introduced during its synthesis may pose potential toxicity risks, especially at high doses. Moreover, the incomplete clearance of MPNs in the body (particularly in the liver and spleen) has raised concerns about its long-term biocompatibility. Therefore, conducting systematic research on the drug release kinetics of MPNs, regulating its biodegradation behavior, and conducting a comprehensive assessment of its biological safety are of great significance for ensuring the clinical feasibility of therapies based on MPNs.

Looking towards the future, MPNs exhibit broad development prospects in the field of tissue regeneration, with future development expected to be driven by the synergy of material design innovation, functional expansion, and clinical translation. Firstly, in terms of material design and synthesis strategies, integrating computer simulations into the research process of MPNs is expected to achieve efficient screening and prediction of material properties. Meanwhile the development of more environmentally friendly, controllable, and scalable synthesis processes, especially by leveraging microfluidic or continuous flow synthesis technologies to break through the limitations of traditional coordination assembly, will significantly enhance the uniformity and scalability of the reaction, laying the foundation for large-scale production in accordance with GMP standards and batch-to-batch consistency. Secondly, expanding the selectio of phenolic ligands and metal ions, and constructing dual-metal or even multi-metal systems, will not only enrich the functional diversity of MPNs, but also enable precise regulation of the stability of the network, degradation kinetics, and biological activity, thereby providing customized candidate material libraries for different tissue microenvironments. On this basis, integrating MPNs with functional biomolecules (such as DNA, RNA, and proteins) is expected to give them new biological functions and enhance the therapeutic effect of tissue regeneration. At the same time, developing intelligent MPNs nanosystems that specifically respond to disease microenvironments (such as pH changes, ROS levels, or enzyme activity) will become an important direction for achieving precise treatment, helping to reduce toxic side effects in the systemic circulation and improving the safety and effectiveness of treatment. Ultimately, in the process of promoting clinical translation, it is urgent to systematically evaluate the long-term biological safety and repair effects of MPNs using large animal model. Early engagement with regulatory authorities is also critical to clarify product classification pathways and approval requirements, thereby ensuring a seamless transition from laboratory research to clinical practice.

Abbreviations

MPNs

Metal polyphenolic networks

TA

Tannic acid

GA

Gallic acid

EC

(−)-epicatechin

ECG

(−)-epicatechin-3-gallate

EGC

(−)-epigallocatechin

EGCG

(−)-epigallocatechin-3-gallate

PAC

Proanthocyanidin

PA

Pyrogallol

Cur

Curcumin

TP

Tea polyphenol

RosA

Rosmarinic acid

PVP

Poly(vinylpyrrolidone)

PEG

Poly(ethylene glycol)

BSA

Bovine serum albumin

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

RONS

Reactive oxygen and nitrogen species

GOx

Glucose oxidase

POD

Peroxidase

SOD

Superoxide dismutase

CAT

Catalase

GPx

Glutathione peroxidase

EPL

-poly-ʟ -lysine

TOB

Tobramycin

BBB

Blood-brain barrier

Aβ

Amyloid beta

PEEK

Polyether ether ketone

OA

Osteoarthritis

SCI

Spinal cord injury

RA

Rheumatoid arthritis

AD

Alzheimer’s disease

IHD

Ischemic heart disease

ECM

Extracellular matrix

VEGF

Vascular endothelial growth factor

CD31

Cell adhesion molecule-1

eNOS

Endothelial nitric oxide synthase

TNF- α

Tumor necrosis factor- α

IL-1 β

Interleukin-1 β

E. coli

Escherichia coli

S. aureus

Staphylococcus aureus

PAO1

Pseudomonas aeruginosa

Author contributions

Meng Luo and Hongzhang Deng worte the main manuscript text.

Funding

This work was jointly supported by the National Key R&D Program of China (2024YFA1212500), National Natural Science Foundation of China (32171320, 82302384, 52503198), Natural Science Basic Research Program of Shaanxi (2025JC-YBQN-1078), Postdoctoral Research Funding Project of Shaanxi (2024BSHSDZZ041), Major Scientific and Technological Innovation Project - Major Scientific and Technological Achievement Transformation Project (Integrated Project of “Education, Science and Technology, and Talent”) (L2025-ZDKJ-ZDCGZH-015), Key Project of the Natural Science Foundation of Shaanxi Province (2025JC-QYCX-066). Xidian University Specially Funded Project for Interdisciplinary Exploration (TZJH2024024), China Postdoctroral Science Foundation (2024M752538), Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20232041), and the Fundamental Research Funds for the Central Universities (XJSJ24081).

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Competing interests

The authors declare no competing interests.