Polyphenol -based controllable assembly platforms for reducing the risk of nonspecific adhesion in vivo for cancer therapy

Abstract

Polyphenols, rich in phenolic structures, are widely found in plants and known for disturbing the cellular oxidative stress and regulating the signal pathways of tumor proliferation and metastasis, making them valuable in cancer therapy. Polyphenols display high adherence due to the presence of phenolic hydroxyl groups, which enables the formation of covalent and non-covalent interactions with different materials. However, nonspecific adhesion of polyphenols carries significant risks in in vivo applications as polyphenols might adhere to proteins and polysaccharides in the bloodstream or gastrointestinal tract, leading to thrombosis and lithiasis. Pre-occupying phenolic hydroxyl groups to construct controllable assembly platforms prior to in vivo application constitutes an effective strategy to enhance biosafety. In this review, we present the potential of polyphenols in cancer therapy and focus on strategies to reduce the risk of nonspecific adhesion. Nanoplatforms, films, and hydrogels are highlighted as the state-of-the-art safe assemblies of polyphenols, providing guidance for the design of safe and sophisticated polyphenol-based platforms, promoting a step forward in the clinical translation of polyphenol-based delivery strategies in cancer therapy.

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1. Introduction

Polyphenols, abundantly present in nature, are a diverse class of organic molecules characterized by their hydroxyl-rich phenolic structures.^1,2 Owing to their ability to regulate various signaling pathways, polyphenols have demonstrated significant potential in anti-tumor therapy, particularly by inhibiting tumor cell cycle progression and inducing apoptosis in tumor cells.^3–6 However, nonspecific binding of polyphenols to biomolecules presents major challenges in their application in vivo.^7–11 This nonspecific interaction can disrupt normal physiological processes, such as inhibiting the enzyme activity or altering the cell membrane permeability.^12,13 Consequently, reducing the nonspecific adhesion risk of polyphenols has become a core challenge to improve their safety and anti-tumor efficacy in vivo.

In recent decades, significant advancements in material platform designs have greatly facilitated the engineering of versatile and safe polyphenol-based delivery systems.^14,15 The phenolic hydroxyl groups in polyphenols play a pivotal role in mediating assembly through the formation of diverse chemical bonds, including metal coordination, π–π interactions, hydrogen bonds, hydrophobic interactions, covalent bonds, and electrostatic interactions.^16–19 To mitigate nonspecific adhesion and enhance safety during in vivo applications, controlled assemblies have been meticulously designed to effectively occupy phenolic hydroxyl groups.²⁰ Among the major delivery platforms, nanoplatforms, films, and hydrogels have been extensively studied due to their excellent bioavailability, biocompatibility, and ability to improve the stability and controlled release of polyphenols.

Breakthroughs in controlled self-assembly technology offer novel perspectives for addressing the nonspecific adhesion of polyphenols. Central to this strategy lies the precise regulation of polyphenolic molecular assembly patterns and surface topological structures through dynamic chemical bonds or external field-responsive moieties (photosensitizers and thermosensitive polymers).^21–24 Rational design enables the self-assembly system to achieve dual critical functions: maintaining “stealth status” during blood circulation via amphiphilic block copolymers or metal ion coordination (e.g., Fe³⁺), optimizing the surface charge distribution and hydrophilic-lipophilic balance to reduce non-target protein binding affinity^25,26 and triggering “active exposure” in tumor microenvironments by leveraging acidic pH, elevated GSH levels, or enzyme-mediated protective layer dissociation to restore phenolic hydroxyl group-mediated targeted adhesion, thereby enhancing cellular uptake and drug release efficiency.^27,28

Through systematic structural engineering, polyphenol-based systems have achieved functional modification and controlled release capabilities while mitigating nonspecific interactions with biomolecules. These advancements substantially reduce off-target effects and ensure effective therapeutic performance in complex tumor microenvironments. This critical review provides an in-depth analysis of the molecular characteristics of polyphenolic compounds and systematically explores strategies to minimize non-specific adhesion and enhance biosafety (Scheme 1). Special emphasis is placed on recent progress in delivery platforms including nanoplatforms, hydrogels, and thin films, highlighting their potential in antitumor therapy (Scheme 2). Furthermore, the intrinsic mechanisms underlying the “functional programmability” of polyphenolic molecules are elucidated. This comprehensive discussion provides interdisciplinary insights with both theoretical depth and practical significance for tumor nanomedicine, accelerating clinical translation of high-safety polyphenol-based therapeutic regimens.

Scheme 1 Schematic of the strategy to turn foes into friends. (A) Universal linking interactions of polyphenols with various materials. (B) Health hazard may occur since the nonspecific adhesion of phenolic hydroxyl groups to biomolecules affects biosafety. (C) Strategies to turn foes into friends: delivery platforms were constructed by a controlled assembly in vitro with the universal linking interactions of polyphenols to achieve application in cancer therapy.

Scheme 2 Schematic of the major delivery platforms for tumor therapy: nanoparticles, hydrogels, and films. Nanoparticles are typically administered via intravenous injection, making them suitable for targeting deep-seated tumors through systemic circulation and accumulation at tumor sites. Hydrogels can be injected locally to form in situ drug depots, offering sustained release for both superficial and deep tumors, especially after surgical resection. Films are primarily applied transdermally for superficial tumors or surgical wounds, enabling localized drug delivery and recurrence prevention.

2. Properties of polyphenols

Polyphenols synergistically drive anti-tumor activities and adhesion properties through their unique chemical structures (e.g., aromatic backbone and modifiable phenolic hydroxyl groups).^29,30 The anti-tumor activity stems from its precise regulation of the core network of tumor proliferation: targeting pro-apoptosis, anti-angiogenesis and metastasis inhibition through the scavenging of reactive oxygen species (ROS) and modulation of Nrf2, NF-κB and other pathways,^31–33 and the adhesion property determines its dynamic binding ability to tumor cell surface receptors (e.g. integrins, CD44) (affecting the risk of tumor cell detachment and colonization) and serves as a molecular “glue” to provide self-assembly sites for multifunctional nanocarriers.^34–36 This structure–function coupling allows polyphenols to act as both therapeutic agents and delivery mediators, demonstrating the potential for “dual-role” applications in tumor intervention.

2.1. Anticancer activity

Polyphenols are well-documented anticancer agents that have been shown to inhibit the growth, proliferation and metastasis of cancer cells.³⁷ This is achieved by regulating a number of signaling molecules and pathways, including the inhibition of the tumor cell cycle, induction of tumor cell apoptosis, antioxidant/promoter of oxidation, inhibition of tumor angiogenesis and downregulation of matrix metalloproteinases (MMPs)^32,38,39 (Scheme 3). These properties make polyphenolic compounds have the potential to intervene in several aspects of cancer development, such as inhibiting the expression of oncogenes, preventing the proliferation and metastasis of tumor cells, and regulating the immune system.

Scheme 3 Schematic of the three different aspects of polyphenols for anticancer activities. (A) Inhibition of cell proliferation: polyphenols inhibit the development of cancer via three aspects: by blocking tumor cell cycle progression, inducing tumor cell apoptosis, and anti-oxidation/pro-oxidation. (B) Inhibition of angiogenesis: polyphenols inhibit IL-8, VEGF, bFGF and other angiogenic factors secreted by malignant tumor cells to repress the formation of new blood vessels. (C) Inhibition of tumor metastasis: polyphenols restrain the progression of tumor metastasis by down-regulating the key proteins such as MMP-2 and MMP-9.

Polyphenols are known to induce cancer cell death effectively through mechanisms such as cell cycle arrest. For instance, resveratrol induces G1 phase arrest by modulating cyclin-dependent kinase (CDK), ultimately leading to apoptosis.^40,41 Polyphenols exhibit dual antioxidant and pro-oxidant effects, which are context-dependent in cancer therapy.^42,43 They inhibit oxidative enzymes, thereby reducing the production of reactive oxygen species (ROS), while also enhancing the activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD).^44,45 These antioxidant effects help mitigate tumor oxidative stress, a critical factor in the progression of many malignancies.⁴⁶ Angiogenesis, critical for tumor growth by supplying oxygen and nutrients and removing waste, is another target of polyphenols.^6,47 Metastasis, the hallmark of malignant tumors and a primary cause of treatment failure, involves the degradation of the basement membrane and extracellular matrix, processes mediated by MMPs.^48,49 Polyphenols such as resveratrol and curcumin have shown the ability to downregulate MMPs, particularly MMP-2 and MMP-9, which are overexpressed in aggressive cancers.^39,50 These findings underscore the potential of polyphenols as effective agents for managing metastatic and recurrent tumors, either as standalone therapeutics or as components of prodrug formulations.

2.2. Adhesion properties

In the late 20th century, the adhesion of polyphenol-containing proteins in mussels attracted the attention of researchers, and the mussel adhesion mechanism was subsequently further explored.^51,52 Studies have found that the hydrophobicity, hydrophilicity and charge transfer regions of dihydroxyphenyl and trihydroxyphenyl were responsible for the high degree of adhesion of polyphenols.⁵³ The phenolic hydroxyl groups of polyphenols enable versatile interactions with various materials, including metal coordination, π–π stacking, hydrogen bonding, hydrophobic effects, electrostatic attractions, and covalent bonding (Scheme 1A).

Polyphenols exhibit the ability to chelate various metal ions such as Fe³⁺, Zn²⁺, and Cu²⁺, forming stable polyphenol–metal complexes.^26,54,55 The aromatic rings in polyphenols enable bonding with various materials via π–π interactions. Polyphenols containing multiple phenolic hydroxyl groups have a characteristic electron-rich π system. Aromatic π–π stacking in polyphenol interactions has been widely reported because assemblies formed via π interactions are more robust and controllable than van der Waals forces formed between alkyl chains.⁵⁶ Among them, π–π interactions formed by inorganic materials and polyphenols are particularly common. Nanoparticles and nanosheets formed via the π–π interactions of polyphenols with inorganic materials such as carbon nanotubes and graphenes exert good effects on cancer regression.^57,58 Hydrogen bonding is another common interaction force between polyphenols and other materials. Owing to relatively high pK_a and multiple protonation states, polyphenols often act as powerful hydrogen donors.⁵⁹ For example, a structurally stable self-assembled supramolecular nanoparticle with a stable structure is formed by interaction between the hydroxyl groups of polyphenols and ether groups in polyether F127.⁶⁰ Polyphenols usually form nanoplatforms with polymers through hydrogen bonds, which effectively shield the adsorption of polyphenols on blood proteins and prolong the residence time of nanoplatforms in vivo. Hydrophobic interaction is considered as the main interaction between proteins and polyphenols.⁶¹ Proteins containing more aliphatic and hydrophobic side chains have more obvious relative advantages in hydrophobic interactions with polyphenols.⁵⁶ Polyphenols and proteins are assembled via hydrophobic interactions in vitro, which avoid the leakage of polyphenols in vivo and ensure the safety of application.

3. Risk of polyphenols in vivo: nonspecific adhesion

The nonspecific adhesion properties of polyphenols in vivo act as a “double-edged sword”, potentially triggering complex pathological risks in multiple physiological systems.^62,63 This non-selective binding capacity is observed not only in the blood and urinary systems but also in luminal tracts such as the gastrointestinal tract, which are directly exposed to the external environment.^64–66 The indiscriminate interaction between polyphenol molecules and biological media may disrupt local microenvironmental homeostasis, leading to clinical issues such as thrombosis, gastric bezoars, and intestinal stones.⁷ The nonspecific adhesion of polyphenols may interfere with the dynamic balance of the coagulation-anticoagulation system via multiple mechanisms. The binding of polyphenols to calcium and magnesium ions in the gastric fluid not only reduces digestive enzyme activity but also generates insoluble salts, which act as nucleation sites for stone formation.^67,68 Upon entering the intestinal environment, the nonspecific adhesion risks of polyphenols exhibit more complex biological effects. Polyphenols may interfere with the emulsification process of fats, and unemulsified fatty acids combine with calcium ions to form insoluble soaps, which are important precursors for intestinal stone formation.⁶⁹

4. Resist the risk of nonspecific adhesion: controllable assembly in vitro

The nonspecific adhesion properties of polyphenols are a key bottleneck limiting their clinical applications. In response to this contradiction, the recent emergence of “in vitro controlled assembly” strategy provides an innovative idea to balance the efficacy and safety of polyphenols.^27,28 To address the risk of non-specific adhesion of phenolic hydroxyl groups, they can be controlled and utilized by assembling them into specific structures such as nanoparticles, membranes and hydrogels (Scheme 4). The core of this strategy lies in the precise structural reorganization or interfacial modification of polyphenol molecules in the in vitro environment via molecular engineering to build composite systems with target recognition capabilities, thereby preempting their non-specific binding sites before entering the body while preserving or enhancing their therapeutic functions. This “pre-programmed” assembly process not only regulates the physicochemical properties of polyphenols, but also provides them with environmentally responsive properties through biomimetic design, enabling them to be dynamically regulated in complex physiological environments. The introduction of spatially hindered groups or the construction of dynamic chemical bonds effectively reduces the stochastic interactions between polyphenols and biomolecules.

Scheme 4 Schematic of the multifaceted role of polyphenol-based platforms in cancer therapy. (A) Polyphenol-based delivery platforms are designed via the interaction of phenolic hydroxyl groups and almost all materials (metal ions, graphene oxide, and small molecules). (B) Applications of polyphenol-based platforms in cancer diagnosis, such as MRI, PAI and PET. (C) Polyphenol-based platforms for monotherapy or combination therapy such as CDT, PTT and PDT.

4.1. Nanoplatforms

Nanoplatforms have been a boon for the cancer theranostics field because of its high drug delivery efficiency and targeted accumulation in tumors. Phenolic hydroxyl groups can be assembled with almost all materials (metal materials, small molecules and polymers) to form nanoplatforms.^25,70–72 In this chapter, we have carried out a study on the latest polyphenol-based nanoplatforms, aiming to design promising platforms in the future.

The preparation of metal-polyphenol nanoparticles is usually realized by a simple mixing method.⁷³ This preparation method has the advantages of easy operation, mild conditions, and no need for complex equipment. An iron-tannic acid composite nanodot (AIE-TFe dot) was synthesized based on AIE (aggregation-induced luminescence) properties by a one-pot method, which utilizes π–π interactions and coordination to achieve assembly (Fig. 1A).⁷⁴ Transmission electron microscopic (TEM) images show the typical core–shell structure of AIE-TFe nanodots with a size of about 100 nm. The core–shell structure of nanodots is shown in Fig. 1B. Elemental mapping analysis showed that the carbon (C) and iron (Fe) elements were uniformly distributed in the resulting nanoparticles (Fig. 1C), confirming the successful construction of iron-tannic acid complexes. An intertumoral self-assembled nanostructured aggregate was synthesized and named FerH using natural polyphenols hematoxylin (HMT) and Fe³⁺ (Fig. 1D).⁷⁵ HMT coordinates with the ferric ions (Fe³⁺) from Ferrlecit™ to form FerH nanocomplex seeds, allowing for a deep tumor penetration. The penetrated FerH nanocomplex seeds possess a dynamic size-growing property based on the stepwise coordination to form interconnected nanoaggregates in the tumor (Fig. 1E), thus endowing a prolonged retention time.

Fig. 1 (A) Schematic of the one-pot synthesis of AIE-TFe dots. (B) TEM images of 2TPEA-AQ@AIE-TFe dots. (C) Elemental mapping images of carbon (C) and iron (Fe) throughout 2TPEA-AQ@AIE-TFe dots by energy-dispersive spectroscopy. (D) Formation of FerH nanocomplex seeds and FerH nanoaggregates. (E) Increase in the hydrodiameter size of FerH during the self-assembly. This figure has been adapted from ref. 74 with permission from Ivyspring international, copyright 2022. (F) PFH was encapsulated in MSN to form MSN-PFH, which encapsulated dopamine on its surface and adsorbed ICG, followed by the adsorption of FA-PEG2000-SH. (G) TEM image. Scale bar = 100 nm. (H) UV spectra. (I) Stability when stored at 4 °C. This figure has been adapted from ref. 16 with permission from Wiley, copyright 2019.

The interaction of non-metal inorganic materials and organic materials with polyphenols involves hydrogen bonding, π–π stacking and hydrophobic interaction and covalent bonds. Non-metal carbon-based materials such as GO and carbon nanotubes have high light absorption efficiency, which are often used as photothermal therapy materials and in combination with polyphenols to inhibit tumor growth.^57,58,76 The polyphenol-based photothermal platform is popular because of its low invasiveness, specificity and remarkable therapeutic effect.

The co-assembly of polyphenols with polymers is another important strategy to construct functional nanoparticles.⁷⁷ Synthetic polymers usually have well-defined structures and tunable molecular weights that provide a stable hydrophobic core suitable for loading hydrophobic drugs, while natural polymers have good biocompatibility and degradability suitable for biomedical applications. Perfluorohexane (PFH)-encapsulated MSNs with an indocyanine green (ICG)–polydopamine (PDA) layer and a poly(ethylene glycol)–folic acid coating (designated as MSNs-PFH@PDA-ICG-PEG-FA) are successfully fabricated to achieve tumor ultrasonic (US)/near-infrared fluorescence (NIRF) imaging as well as photothermal therapy (PTT)/photodynamic therapy (PDT) (Fig. 1F and G).¹⁶ MSNs-PFH@PDA-ICG-PEG-FA exhibit good monodispersity with a high ICG loading, significantly enhancing ICG photostability (Fig. 1H and I). PDA can be efficiently loaded with aromatic ICG via π–π stacking, which effectively enhances the NIR-induced response and further immobilizes PEG-folic acid (FA), to enhance and bind the antitumor effect.

Polyphenol molecules are rich in phenolic hydroxyl groups and aromatic ring structures, which can dynamically bind to proteins (e.g., albumin, and casein, etc.) through various mechanisms, such as hydrogen bonding, hydrophobic interactions, electrostatic attraction, and covalent cross-linking, to form structurally stable and functionally tunable nanoparticles.^78,79 Unlike traditional synthetic polymers or lipid nanoparticles, polyphenol–protein nanoparticles not only retain the natural bioactivities of proteins (e.g., targeting and enzyme catalytic function), but also provide additional therapeutic functions to the system through the antioxidant and anti-inflammatory properties of polyphenols, which show broad application prospects in the fields of anti-tumor, anti-infection, and immunomodulation.^80,81 A cancer cell membrane-coated biomimetic nanoplatform (termed as mPAGT) was designed via a simple and versatile polyphenol-mediated coating strategy for a catalytic cascade-enhanced tumor-targeted combination therapy (Fig. 2).⁸² The nano-photosensitizer porphyrin MOF was first prepared as a multifunctional nanosystem (defined as PCN NPs). Then the endogenous NO donor L-Arg was loaded into the framework of PCN NPs to obtain PA NPs. Subsequently, GOx was coated onto the surface of PA NPs to form a core–shell architecture (termed PAGT NPs) via the interactions between protein and polyphenol (tannic acid, TA). Finally, the PAGT NPs were further biomimetic decoration through coated a layer of purified murine breast cancer(4T1) cell membrane and obtained the resulting nanoplatforms mPAGT NPs.

Fig. 2 (A) Preparation procedure of mPAGT NPs and lethal mechanism of the catalytic cascade-enhanced synergistic therapy. (B) TEM images of mPAGT NPs. (C) Zeta potential of PCN, PA, PGT and PAGT NPs. (D) UV-vis absorption spectra of the aqueous solution. (E) SDS-PAGE protein analysis of 4T1 cell membrane, GOx and mPGT NPs. (F) Schematic of the reaction by PAGT NPs. (G) Generation of H₂O₂ over time. (H) pH value changes of solutions after treatment with mPGT NPs. (I) ¹O₂ generation of various samples with DPBF as the probe. (J) NO generation-dependent Glu concentration. (K) NO release of mPAGT NPs under various treatments. This figure has been adapted from ref. 80 with permission from Elsevier, copyright 2022.

The self-assembly of polyphenols to form nanoparticles demonstrates the unique advantages of natural molecules on the nanoscale. The abundant phenolic hydroxyl groups and aromatic rings in polyphenols confer strong intermolecular interactions and enable precise self-assembly via non-covalent forces, such as dynamic coordination and hydrogen bonding networks. This bottom-up assembly strategy eliminates the need for complex equipment and harsh chemical reagents typically required in conventional nanomaterial fabrication. At the functional design level, the interfacial properties of polyphenol nanoparticles are highly tunable-by regulating the pH, ionic strength or introducing template molecules in the assembly environment, the size distribution, surface charge and pore structure of the particles can be precisely controlled, thus adapting to the needs of different physiological environments. This structural flexibility enables the particles to be used as drug carriers for the encapsulation and controlled release of active ingredients, as well as for the integration of targeting groups through surface modification to significantly enhance bioavailability.

4.2. Films

Using films as a high-safety strategy for soft tissue repair after tumor resection can cover the tumor resection wound and help spread the loaded drug.^83,84 Polyphenol-based films are used in the edge of the fixed after tumor resection to inhibit the local recurrence after tumor resection.^85,86 Moreover, the film loaded with drugs effectively inhibited the growth of local tumors via transplantation to specific sites.

A bacterial cellulose film with good anticancer effects has been successfully developed.^87,88 The film was rich in a large number of polyphenolic compounds, such as alpha-mangosteen and gallic acid, showing good anti-cancer properties. Moreover, the film was developed as a drug carrier for its good loading performance and drug release control function. Anti-cancer performance tests demonstrated that the films showed obvious toxicity to melanoma and breast cancer cells, whilst it significantly inhibited skin infection by Gram-positive bacteria. It is worth mentioning that the film had good biocompatibility to normal fibroblasts and keratinocytes. Curcumin is characterized by powerful antioxidant and anticancer activities, but its low solubility and poor stability also limit its further applications in biomedicine, such as cancer therapy.⁸⁹ Films, as topical drug delivery forms, have shown great advantages in protecting the biological activity of curcumin.²⁰ Curcumin-loaded films prepared from bacterial cellulose, alginate and gelatin showed strong antibacterial activity and anti-tumor activity against oral cancer (Fig. 3). Moreover, the film exhibited high safety and good biocompatibility in human keratinocytes and human gingival fibroblasts. Due to its strong adhesion, the film is of great medical value as a wound dressing and skin adhesive patch. In addition to curcumin, another olive polyphenol compound achieved good results in skin cancer treatment. A double layer film prepared by combining the olive polyphenol compound with sodium alginate can effectively inhibit breast cancer and skin cancer.

Fig. 3 (A) Schematic of the preparation of cellulose/alginate/gelatin film. (B) Morphology of the film after 48 h of infiltration in artificial saliva and PBS. (C) Attachment to skin and flexibility of film. Reproduced with permission. (D) Water contact angles of BCAGG-C1, BCAGG-C2, BCAGG-C3 and BCAGG-C4. (E) Film attachment to skin; film flexibility. This figure has been adapted from ref. 20 with permission from Multidisciplinary Digital Publishing Institute, copyright 2020.

The formation of polyphenolic films usually depends on their self-assembly ability or synergistic cross-linking with other components. Tannins can form metal-polyphenol coordination networks (MPNs) via the coordination of neighboring phenolic hydroxyl groups with metal ions such as Fe³⁺ and Cu²⁺, for rapid film deposition at solid–liquid interfaces (e.g., surgical instruments or tissue surfaces).^90,91 Polyphenolic films can be used as localized drug reservoirs for long-lasting controlled release via microenvironmental response mechanisms. After the tannic acid-Fe³⁺ ligand membrane is loaded with cisplatin and implanted into the postoperative tumor cavity, in the weakly acidic tumor microenvironment, Fe³⁺ is reduced to Fe²⁺, leading to the ligand bond rupture and sustained release of cisplatin.⁹² A thickness-adjustable film was prepared, which could be self-assembled in situ on bladder cancer tissues and loaded with the chemotherapeutic drug gemcitabine through the coordination of TA and Fe³⁺.⁹¹ Unsurprisingly, the thickness-adjustable TA@Fe films could effectively prolong the residence time of the anticancer drug in the bladder and achieve sustained release of the anticancer drug⁶³ (Fig. 4). As expected, the TA@Fe film with adjustable thickness could effectively prolong the residence time of anticancer drugs in the bladder and realize sustained release of anticancer drugs.

Fig. 4 (A) Schematic illustration of one-step in situ self-assembly of TA@Fe film loading with gemcitabine for long-term intravesical therapy in bladder tumor. (B) Schematic illustration of the preparation method for the TA@Fe film with different cycles. (C) Thickness of the TA@Fe film on mica at different coating cycles characterized by an ellipsometer. (D) Force–deformation approach curves for large deformations of the different force cycles on the TA@Fe film (n = 50, 100, 500, and 1000). (E) GEM loading of the TA@Fe film-coated bladder tissue at different cycles in vitro. (F) Drug release rate of the GEM-loaded TA@Fe film on bladder tissue in human urine at different pHs. (G) Fluorescence imaging of the FITC-loaded TA@Fe film on pig bladder tissue. Scale bar: 5 μm. (H) AFM image of TA@Fe film on mica. (I) TA@Fe film retention imaging in the bladder characterized by MRI. (J) Thickness of the TA@Fe film in vivo characterized by MRI. **p < 0.005 and ***p < 0.001. This figure has been adapted from Ref. 87 with permission from American Chemical Society, copyright 2022.

Polyphenol films are promising anticancer composites. Due to their good adhesion, they can be used as a patch to directly cover on the wound after tumor resection to effectively promote wound healing and prevent recurrence. Polyphenol-based films are used in a mild and effective treatment strategy for soft tissue carcinoma, especially they show broad potential applications in skin cancer and superficial breast cancer treatment.

4.3. Hydrogels

Polyphenols have shown remarkable potential in the construction of functional hydrogels for tumor therapy in recent years due to their unique chemical structures and biological activities. Polyphenol molecules are rich in neighboring phenolic hydroxyl groups and aromatic ring structures, which can form three-dimensional network structures with other components (e.g., polymers, proteins, polysaccharides, or metal ions) via various mechanisms such as hydrogen bonding, π–π stacking, hydrophobic interactions, metal coordination, and covalent cross-linking, and thus, hydrogels with adjustable mechanical properties, environmental responsiveness, and biofunctionality can be prepared.^{83,84,93–95} These hydrogels can be used as drug delivery carriers for localized tumor therapy and for enhancing the anti-tumor effect through the antioxidant, anti-inflammatory and immunomodulatory activities of polyphenols themselves. Compared with traditional nanoparticles or membrane materials, hydrogel systems have unique advantages in terms of local retention, controlled drug release and microenvironmental regulation, which are especially suitable for post-surgical tumor filling, in situ injection or targeted isolation scenarios.

By embedding photothermal agents (e.g., ICG and gold nanoparticles) or photosensitizers (e.g., methylene blue, MB) into polyphenol-based hydrogels, they can be endowed with light-responsive functions.^96,97 The MB-loaded polyphenol-based hydrogel can generate reactive oxygen species (ROS) under laser excitation, destroying the tumor mitochondrial function through photodynamic therapy (PDT) and reducing the damage to normal tissues by combining with the antioxidant protective effect of polyphenols. Boronate ester linkages (between APBA and dopamine) and dopamine polymerization (by controlling pH) were introduced as the major gel cross-linking mechanisms for fabricating a hydrogel system in a study (Fig. 5).⁹⁸ Engagement of immediate gelation based on boronate ester bonds and elaborate pH control made an optimized hydrogel system for peritumoral injection. ERT (as a receptor tyrosine kinase inhibitor for EGFR) was encapsulated in a PLGA MS, and further, it was embedded in an HP9/HD cross-linked hydrogel for longer accumulation in a tumor region. It is expected that the ERT MS-embedded HP9/HD hydrogel can provide sustained and locoregional delivery of ERT and enhanced cancer curing efficiencies. Sustained release, local delivery, and tyrosine kinase targetability of ERT may dramatically attenuate unwanted toxicities and maintain sufficient tumor-suppressive capabilities. It is surmised that the designed hydrogel system may be a powerful candidate for selective and safe treatment of lung cancer.

Fig. 5 (A) Scheme of a pH-controlled cross-linked hydrogel system including ERT MS for peritumoral injection. (B) Continuous release of drugs in situ by injectable temperature-sensitive hydrogels. Reproduced with permission. (C) Self-healing features of the HP9/HD cross-linked hydrogel verified by a stretchability test. Images at cut, attached for 0 h, attached for 1 h, and stretched for 1 h are displayed. (D) Injectability test of the HP9/HD/ERT MS hydrogel (containing methylene blue) using a single syringe system. (E) ERT release profiles from ERT MS and HP9/HD/ERT MS groups. Each point indicates mean ± SD (n = 5). (F) SEM images of the lyophilized HP/HD, HP9/HD, and HP9/HD/ERT MS specimens. Scale bar = 20 μm. This figure has been adapted from ref. 95 with permission from the American Chemical Society, copyright 2021.

The formation of polyphenol-based hydrogels usually relies on dynamic or covalent cross-linking interactions between polyphenols and other components. For example, tannins can form stable coordination bonds with metal ions, such as Fe³⁺ and Cu²⁺, through their neighboring phenolic hydroxyl groups to construct metal-polyphenol coordination networks (MPNs), which can be rapidly gelated under mild conditions (e.g., room temperature and neutral pH).^99,100 A synergistic treatment was developed that utilized the oral delivery of DSF and an injectable polyphenol–copper (PA–Cu) hydrogel loaded with the glutamine uptake inhibitor 2-amino-4-bis(phenoxymethyl)aminobutane (V9302) (Fig. 6).¹⁰¹ The injectable hydrogels were synthesized via the Schiff base reaction of hydroxypropyl chitosan (HPCS) with a PA-Cu reversible cross-linking agent. Because of the dynamic coordination between PA and Cu, the PA-Cu/HPCS hydrogel gradually releases Cu²⁺, forming CuET with DSF. The phenolic hydroxyl groups in PA can form coordination bonds with Cu²⁺. These groups can be oxidized to a quinone structure while reducing metal ions. The PA, Cu²⁺ and benzoquinone structures formed by the oxidation of PA with H₂O₂ do not have significant absorption peaks in the spectral range of 600–700 nm, whereas significant absorption peaks are observed in this range for PA-Cu. This suggests that PA and Cu²⁺ form complexes only through coordinated interactions. By adjusting the ratio of PA-Cu to HPCS, it was found that the Cu content in the hydrogel was proportional to the PA-Cu content. Fourier transform infrared (FTIR) spectroscopy was performed to detect the characteristic functional groups in the PA-Cu/HPCS hydrogels. As the aldehyde ratio increased, the swelling of the hydrogel decreased, indicating an increase in its cross-linking density. The formation of the Schiff base structure was verified by the absence of a peak at 1594 cm⁻¹, the peak associated with the ring vibrational absorption of benzene-C double-bonded to the O atom of PA in PA-Cu/HPCS hydrogels, and a new absorption peak at 1267 cm⁻¹, belonging to the C atom double-bonded to N.

Fig. 6 (A) Schematic of the preparation of the V9302@DSPE-PEG-loaded PA-Cu/HPCS/V9302 hydrogel. (B) UV-Vis spectra of PA-Cu and different molecules. (C) Content of Cu in the hydrogel of different ratios of PA-Cu and HPCS (n = 3). (D) Swelling ratio of hydrogels with different ratios of PA-Cu and HPCS (n = 3). (E) FTIR spectra of hydrogel and different molecules. (F) Injectability of PA-Cu/HPCS hydrogels. (G) SEM image of the PA-Cu/HPCS/V9302 hydrogel. This figure has been adapted from ref. 98 with permission from Elsevier, copyright 2025.

Polyphenols form functionalized hydrogels via dynamic self-assembly, showing significant advantages in enhancing the safety of material applications. Its three-dimensional network structure exhibits excellent biocompatibility and forms an adaptive cross-linking system via reversible intermolecular hydrogen bonding and π–π stacking, enabling dynamic responses to physiological changes for precise regulation. In the medical field, this dynamic characteristic allows the hydrogel to fit irregular wound morphology and increase application scenarios.

5. Adhesion-blocking efficacy of platform

Nonspecific adhesion remains a critical limitation in tumor-targeted drug delivery, often leading to off-target accumulation, rapid clearance, or unintended immune activation.^102,103 Various platforms—nanoparticles, films, and hydrogels—have been developed to mitigate this issue by employing distinct anti-fouling strategies, tailored to their structural characteristics and therapeutic applications.

Tumor-targeted nanoparticles frequently suffer from rapid opsonization and clearance. To address this, surface masking strategies are often used to shield reactive groups such as phenolic hydroxyls, which can otherwise interact with plasma proteins.¹⁰⁴ Polyphenol–metal coordination, PEGylation, or zwitterionic coatings are commonly employed to build hydration shells or dynamic layers that prevent protein corona formation.¹⁰⁵ For instance, nanoparticles modified with PEG-TA-Fe³⁺ complexes have been shown to reduce serum protein adsorption by approximately 70%,¹⁰⁵ prolonging circulation time and enhancing tumor accumulation through EPR or active ligand-mediated targeting.

In post-surgical tumor therapy, bioadhesive films serve as local delivery platforms. To prevent off-target cell adhesion and fibrotic encapsulation, many films incorporate hydrophilic or zwitterionic interfaces, or microstructure topographies that discourage cell settlement. For example, gallic acid (GA) films coated with poly(2-ethyl-2-oxazoline) (PEtOx) and poly(methyl methacrylate) (PMMA) exhibited significantly reduced protein adhesion (∼70% reduction) compared to unmodified films.¹⁰⁶

TA–Fe coordination hydrogels possess high water content and tunable porosity, making them particularly effective at resisting nonspecific protein adsorption. The reversible coordination between tannic acid and Fe³⁺ enables the formation of a dynamic, hydrated surface that impedes the adsorption of proteins such as mucins and albumin. Recent studies have shown that TA–Fe hydrogels can reduce mucin and albumin adsorption by over 71%.¹⁰⁷ This anti-fouling behavior is crucial for maintaining the bioactivity of delivered therapeutics and enhancing immune cell infiltration within the TME.

Recent studies have highlighted that polyethylene glycol (PEG), while widely used to enhance nanoparticle circulation and reduce nonspecific protein adsorption, can strongly interact with polyphenols via hydrogen bonding and π–π stacking, potentially masking their phenolic groups and impairing subsequent functional activation.^108,109 This shielding effect, although beneficial for systemic stealth, may hinder key interactions in the tumor microenvironment. Notably, in the context of immunotherapy, polyphenol-mediated adhesion can be advantageous by promoting immune cell association, uptake, and activation. For instance, polyphenol-based hydrogels and scaffolds have been shown to enhance dendritic cell activation and macrophage polarization through adhesive and redox-active interfaces.^110,111 Therefore, rational modulation of polyphenol accessibility—shielded during circulation but exposed at target sites—offers a promising strategy to balance immune evasion and activation.

6. Role of polyphenols in controlled assembly platforms

Polyphenols exhibit unique dual properties in the assembly system, both as the core assembly unit for building functional nanostructures and as active ingredients directly involved in the antitumor process.^112,113 The dense distribution of phenolic hydroxyl groups and aromatic rings in the molecular structure of polyphenols endows them with strong molecular recognition and self-assembly capabilities. When interacting with metal ions, polymers or biomolecules, polyphenols form a stable structure via dynamic coordination bonding, π–π stacking and hydrogen bonding networks and endow the nanocarriers with intelligent response properties.²⁸ At the level of anti-tumor mechanism, the chemical properties of polyphenols and the physical properties of nanostructures generate multidimensional synergistic effects. Its inherent antioxidant activity can reverse the oxidative stress tolerance of tumor cells and enhance the sensitivity of chemotherapeutic drugs by scavenging reactive oxygen species (ROS) in the tumor microenvironment.^114,115 This combination of biological effect and physical drug-carrying function makes polyphenol-based assembled materials show the therapeutic advantage of “carrier–drug integration”.

6.1. As anti-cancer molecules

Polyphenols as anti-cancer molecular drugs retain anti-cancer activity in delivery platforms with the capacities including blocking tumor cell cycle progression.⁸⁸ Polyphenols are encapsulated in hydrogels as anticancer drugs for on-demand controlled release at specific sites. PTT therapy is a local safe therapy for killing tumor cells, and the mechanism is that the high temperature caused by near-infrared irradiation of photothermal materials results in tumor cell apoptosis and death.^116,117 Polyphenolic metal oxide combination showed an excellent photothermal therapy effect. The polyphenol metal oxide combination also had good chemokinetic therapeutic effects, in particular the PTT/CDT combination therapy endowed the material with a strong anti-tumor effect.¹¹⁸ PDT is a treatment that utilizes photosensitizers to produce singlet oxygen under laser irradiation to kill tumor cells.¹¹⁹ Compared with traditional doxorubicin or cisplatin, natural gossypol from cotton plants exhibits anti-cancer properties without significant systemic side effects.¹²⁰ The gossypol nanoparticles containing the photosensitizer Ce6 have been successfully designed to induce ICD performance by initiating PDT with a 606 nm laser (Fig. 7).¹²¹ The nanoparticles combined with PD-L1 antibodies (an ICB agent) were applied to enhance immune stimulation, which achieved remarkable success in inhibiting tumor proliferation and metastasis. GA, a naturally occurring polyphenol compound, has demonstrated significant coordination ability and anti-tumor activity due to its molecular structure, which contains multiple hydroxyl groups.¹²² GA induces apoptosis by disrupting the mitochondrial membrane integrity and activating caspase-3, as well as causing cell cycle arrest at the Gap Phase 2/Metaphase (G2/M) phase.

Fig. 7 (A) PFGs combined with PD-L1 checkpoint blockade for immune response enhancement inhibiting tumor proliferation and metastasis. DAMPs: damage-associated molecular patterns. TAAs: tumor-associated antigens. (B) Generation of ROS was detected by an H2DCFDA probe in 4T1 cells treated by PFGs with or without laser irradiation. Scale bar: 10 μm. (C) CRT expression after various treatments. (D) HMGB1 release after various treatments. (D) Primary tumor or (E) ATP secretion in the medium after various treatments. Scale bar: 10 μm. This figure has been adapted from ref. 108 with permission from Wiley, copyright 2020. (F) Flow cytometry analysis of the proportion of 4T1 cells in G0/G1, S, and G2/M phases after different treatments. (G) Flow cytometry quantitative results of F. This figure has been adapted from ref. 109 with permission from Elsevier, copyright 2025.

6.2. As assembly molecules

Polyphenols exhibit excellent “structure-directed” functionalities in controllable self-assembly platforms due to their unique molecular conformations and dynamic bonding capabilities. Catechol/catechol groups act as molecular hubs that can form dynamic crosslinked networks with metal ions, polymers or biomolecules via multiple non-covalent interactions (hydrogen bonding, π–π stacking, and hydrophobic interactions).^123–125 Multiple o-phenyltriol units in tannic acid molecules can form high-density coordination bonds with Fe³⁺ (each tannic acid molecule binds an average of 8 Fe³⁺) to build pH-responsive nano-network structures. This coordination remains stable at physiological pH (7.4), while dissociation occurs in the slightly acidic environment of tumors (pH 6.5), enabling precise drug release.^126,127 Polyphenol metal copolymer nanoparticles were successfully assembled using anthocyanins and iron ions extracted from blue honeysuckle (Fig. 8).¹²⁸ These multifunctional particles can efficiently accumulate in tumors via the EPR effect, thus enabling both MR imaging and PA imaging for tumor diagnostic strategies. In addition, NIR/photothermal imaging allows the visualization of in vivo location and tumor size, facilitating local tumor diagnosis and treatment in combination with photothermal therapy.

Fig. 8 Schematic of multifunctional therapeutic nanoparticle derivatives extracted from fruits in cancer diagnosis. (A) Schematic of the construction of multifunctional nanoparticles composed of anthocyanins (ACN), iron ions and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) copolymers. (B) Therapeutic and diagnostic applications of biocompatible nanoplatforms in oncology. (C and D) Photoacoustic (PA) and magnetic resonance (MR) imaging of FeAP-NPs at graded concentrations (0.1–5.0 mM) in vitro. (E) Longitudinal PA monitoring of tumor xenografts following FeAP-NP administration (2–48 h post-injection), with dashed contours delineating neoplastic regions. (F) Quantitative correlation of FeAP-NPs’ R₁ relaxivity with Fe³⁺ molarity. This figure has been adapted from ref. 115 with permission from the American Chemical Society, copyright 2020.

7. Controlled assembly platforms improve biosafety effects

The polyphenol-based controllable assembly platform can block the direct contact between polyphenol molecules and their surrounding environment in vitro by utilizing phenolic hydroxyl groups, which helps reduce the non-specific interactions between polyphenol molecules and cellular or protein biomolecules, thereby improving their biocompatibility. Additionally, in applications such as drug delivery, the carriers formed by polyphenol self-assembly can be modified with specific surface modifications to enhance their targeting to target cells or tissues, thereby reducing non-targeted adhesion and ultimately significantly reducing the risk of non-discriminatory polyphenol adhesion.

Free polyphenols at high concentrations may exhibit toxicity to normal cells and tissues, primarily due to their strong antioxidant properties, which can disrupt cellular redox balance.¹²⁹ Additionally, free polyphenols are prone to rapid degradation under physiological conditions, with degradation products potentially exhibiting toxicity, thereby further increasing tissue damage risks. Through self-assembly techniques, polyphenol molecules can form stable nanoparticles, thin films, or hydrogels, effectively reducing direct contact with normal cells. Polyphenol–copper nanozymes form stable coordination structures with copper ions, preventing the burst release of polyphenols while modulating free radical generation through their antioxidant enzyme activity, thereby reducing oxidative damage to normal cells.¹⁰⁰ Moreover, the surface of self-assembled polyphenol nanoparticles can be functionalized with polyethylene glycol (PEG) or hyaluronic acid to further minimize nonspecific interactions with cell membranes, thereby reducing cytotoxicity associated with direct contact. Studies have also shown that PEGylated polyphenol nanoparticles not only reduce immune recognition and hepatotoxicity but also extend circulation time in vivo, thereby alleviating the metabolic burden on the liver and kidneys.¹³⁰ Zn²⁺-EGCG MPNs was prepared based on the interaction between EGCG and ZIF-8, nontoxic and biocompatible MOFs, and termed EGCG–ZIF-8 nanoparticles (EZ NPs) for tumor immunotherapy (Fig. 9A).¹³¹ There was no significant change in body weight of mice when applied in vivo. Hepatic, renal, and hematologic toxicities were further evaluated by serum biochemical analysis and whole blood tests, which showed no significant toxicity in the liver, kidney, and blood of the EZP NPs (Fig. 9B–K), suggesting a high degree of biosafety.

Fig. 9 (A) Schematic representation of the Deigned and Prepared EZP Nanoparticle for Cancer Immunotherapy. (B) Body weight. Serumbiochemistry assay includes, (C) Creatinine as spleen function markers and (D) UREA, (E) Alanine aminotransferase (ALT) as liver function marker, and (F) aspartate aminotransferase (AST) as heart function marker. (G) Blood levels of white blood cells (WBC), red blood cells (RBC), platelets (PLT), (H) hemoglobin (HGB), (I) hematocrit (HCT), (J) mean corpuscular volume (MCV), and (K) mean corpuscular hemoglobin concentration (MCHC) were shown as complete blood panel test results.

Self-assembly techniques optimize the surface chemical properties of polyphenols and shield their active groups, significantly reducing the risk of nonspecific adhesion. Functional modifications of polyphenol materials, such as their combination with biocompatible materials like hyaluronic acid or chitosan, further enhance biosafety. Studies demonstrate that hyaluronic acid-polyphenol hydrogels exhibit excellent tissue compatibility in animal models, are completely non-toxic to host tissues, and significantly promote healing processes.¹³² Hydrogen-bonded tannic acid-based nanoparticles (PTX-NPs) were synthesized via flash nanoprecipitation (FNP), a scalable methodology enabling precise nanocarrier fabrication (Fig. 10).¹³³ Leveraging intermolecular hydrogen bonding, pH-responsive characteristics, and P-gp inhibitory activity, this system demonstrated multifunctional capabilities including enhanced PTX encapsulation (12.8% ± 1.2%), site-specific intestinal release (89.4% cumulative colonic delivery), and optimized oral bioavailability (25.6% relative to intravenous administration). In a breast cancer xenograft model, orally administered PTX-NP exhibited comparable tumor suppression efficacy (68.3% TGI) to injectable formulations (71.5% TGI, p > 0.05) without dose-dependent toxicity. Systemic safety assessments revealed no statistically significant alterations in hepatic enzymes across 10–20 mg kg⁻¹ dosage groups versus controls. Histopathological evaluation further confirmed intact tissue architecture in vital organs (heart, liver, spleen, lungs, and kidneys), with no observable drug-induced inflammatory or fibrotic lesions.

Fig. 10 (A) Illustration of flash nanoprecipitation (FNP)-driven scalable fabrication of paclitaxel-loaded tannic acid/polyvinylpyrrolidone nanoparticles (PTX-NPs). (B) Histopathological evaluation of vital organs (heart, liver, spleen, lungs, and kidneys) via hematoxylin–eosin (H&E) staining post treatment. Serum biochemical profiles assessing (C) hepatic function (AST, ALT, and ALP) and (D) renal biomarkers (BUN and CRE) across experimental cohorts. This figure has been adapted from ref. 120 with permission from Wiley, copyright 2020.

8. Clinical prospects

We summarize the typical clinical drugs reviewed (Table 1). The anticancer activity of polyphenols has been widely concerned by researchers, and many studies have been conducted in clinical translation. In clinical trials for the treatment of colorectal cancer, resveratrol was shown to induce caspase-dependent intrinsic apoptosis and regulate the wnt signaling pathway, inducing tumor cell death and thereby reducing tumor growth (NCT00920803, NCT00433576 and NCT002556334).¹³⁴ Curcumin has also been extensively studied in clinical trials in colorectal, pancreatic, breast and hematological malignancies (NCT00094445 and NCT02095717) and has been shown to be non-toxic, safe and tolerated at high doses (8 g d⁻¹).¹³⁴ Various studies of polyphenol formulations have been carried out in different stages of clinical practice and effective therapeutic effects have been achieved; however, there are still inevitable defects, such as low bioavailability, poor solubility and strong non-specific adhesion biosafety, which lead to many risk problems in applications. Nanoparticle and hydrogel platforms have been developed to be tested clinically to treat cancer, and these platforms can enhance survival and improve postoperative outcomes;^135–137 however, applications are often accompanied by neutropenia.

Table 1 Therapeutic applications in clinical contexts

Types	Names	Method	Indication	Observations	Ref.
Free polyphenols	Resveratrol	Oral	Colon cancer; neuroendocrine tumors; liver cancer; colorectal adenocarcinoma; colorectal adenocarcinoma	i: Inhibition of tumor growth; ii: Inducing cell apoptosis and inhibit cell proliferation, invasion and metastasis; iii: Regulation of COX-2 and M1G expression levels and Notch signaling	134
	Curcumin	Oral	Adenocarcinoma and advanced pancreatic cancer; breast cancers	i: Downregulation of NF-κB, pSTAT3 and COX-2; ii: Safety	138
	Silibinin	Oral	Hepatocellular carcinoma; breast cancer; colorectal Cancer; prostate cancer	i: Reducing markers of liver injury, levels of inflammatory cytokines and markers of tumorigenesis; ii: High safety; iii: Combination improves biochemical markers associated with prostate cancer.	139
	Icaritin	Oral	Advanced HCC; HCC	i: Safety; ii: Immunomodulation	140
Nanoparticles	Albumin-bound paclitaxel	Intravenous injection	Hepatocellular carcinoma	i: Increase overall survival; ii: Neutropenia	135
	Doxorubicin-loaded nanoparticles	Intravenous injection	Early breast cancer	i: Good pathological response; ii: Neutropenia	141
Hydrogels	Histrelin-hydrogels	Subcutaneous	Palliative treatment of prostate cancer	Inhibiting LH levels and testosterone at 4 weeks and maintaining these levels for 52 weeks	136 and 137

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9. Conclusion

This paper summarized the potential of polyphenols in cancer therapy and their controlled self-assembly platforms in reducing the risk of nonspecific adhesion. Polyphenols, due to their rich phenolic hydroxyl structure, exhibit significant biological activities such as antiproliferative, apoptosis-inducing and oxidative stress-regulating functions in antitumor therapy. However, polyphenols present significant nonspecific adhesion risks during in vivo applications, which not only limit their therapeutic effects but may also trigger adverse reactions such as immune response, coagulation, and tissue damage. Therefore, the development of controlled self-assembly platforms to reduce the nonspecific adhesion of polyphenols is an important strategy to enhance their biosafety and therapeutic efficacy. The research progress of modulating the spatial structure and interfacial properties of polyphenol molecules through material platforms such as nanoplatforms, thin films, and hydrogels so as to effectively occupy their phenolic hydroxyl groups and reduce the risk of nonspecific adhesion is analyzed. These controlled self-assembly platforms not only significantly enhance the targeting and bioavailability of polyphenols in the tumor microenvironment, but also further enhance the anti-tumor activity of polyphenols via multiple combined therapeutic strategies (e.g., photothermal therapy, photodynamic therapy, and chemodynamic therapy). Although polyphenol-based controlled self-assembly platforms have achieved remarkable results in vitro and in animal models, they still face many challenges in clinical applications. First, the biocompatibility and safety of polyphenol-based materials in different individuals and disease models need to be further systematically verified;^142,143 second, how to achieve more precise targeted release and dynamic response in the in vivo environment is an important direction for future research. In addition, the development of polyphenol-based smart nanoplatforms, combined with cutting-edge technologies such as immunotherapy and gene therapy, will be expected to significantly enhance the clinical translational applications of polyphenols in cancer therapy. By continuously optimizing the design and preparation process of polyphenol-based materials, it is expected to further promote their wide application in the precision treatment of tumors for the benefit of patients.

Conflicts of interest

The authors declare no conflict of interest.

Data availability

Data are available from the authors upon request.

The data that support the findings of this study are available from the corresponding author, Ya Liu, upon reasonable request.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (32471453); National Key R&D Program of China (2024YFD2402105); Qingdao Marine Science and Technology Center Shandong Province Special Fund “Frontier Technology Free Exploration” (No. 12-04) and Large Instrument Sharing Platform of College of Marine Life Sciences, Ocean University of China.

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Footnote

† These authors contributed equally to this work.

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