Wound Microenvironment Research Articles

Modification of mesenchymal stromal cells with silibinin-loaded PLGA nanoparticles improves their therapeutic efficacy for cutaneous wound repair

The use of mesenchymal stromal cells (MSCs) for treating chronic inflammatory disorders, wounds, and ischemia-reperfusion injuries has shown improved healing efficacy. However, the poor survival rate of transplanted cells due to oxidative stress in injured or inflamed tissue remains a significant concern for MSC-based therapies. In this study, we developed a new approach to protect MSCs from oxidative stress, thereby improving their survival in a wound microenvironment and enhancing their therapeutic effect. We produced PLGA nanoparticles loaded with the cytoprotective phytochemical silibinin (SBN), and used them to modify MSCs. Upon internalization, these nanoformulations released SBN, activating the Nrf2/ARE signaling pathway, resulting in threefold reduction in intracellular ROS content and improved cell survival under oxidative stress conditions. Modification of MSCs with SBN-loaded PLGA nanoparticles increased their survival upon transplantation to full-thickness cutaneous wounds and improved wound healing. This study suggests that MSC modification with cytoprotective nanoparticles could be a promising approach for improving wound healing.

PH‑responsive nanozyme cascade catalysis: A strategy of BiVO4 application for modulation of pathological wound microenvironment

Persistent inflammation and bacterial infection commonly occur during the wound healing process, necessitating urgent development of effective strategies for treating drug-resistant bacterial infections. In this study, bismuth vanadate (BiVO4) was successfully synthesized as an antibacterial agent that promotes wound healing. Through In vitro antibacterial experiments, it was observed that the prepared BiVO4 exhibited excellent performance in catalyzing H2O2 to produce hydroxyl radicals (OH) at a lower concentration (0.2 mg mL−1), resulting in significant antibacterial effects against Gram-negative Extended-Spectrum β-Lactamases-Producing Escherichia coli (ESBL-E. coli) strains. Furthermore, biosafety tests, cell scratch experiments, and ESBL-E. coli infected wound rat model experiments demonstrated high biocompatibility of BiVO4 with a cell survival rate exceeding 85 %. Additionally, BiVO4 promoted the production of vascular endothelial growth factors and fibroblasts migration while contributing to collagen production, effectively facilitating immune reconstruction at the wound site. By integrating peroxidase (POD)-like under acidic conditions (pH 4) and catalase (CAT)-like catalytic activities at under neutral conditions (pH 7), BiVO4 exhibited the ability to activate free radical sterilization and accelerate wound healing by activating O2. Therefore, our findings provide evidence for a dual enzyme regulatory mechanism involving antibacterial properties and promotion of wound tissue reconstruction for potential application in both antibacterial treatment and wound healing.

Marine‐Derived Nanozyme‐Crosslinked Self‐Adaptive Hydrogels for Programmed Regulating the Regeneration Process

AbstractSelf‐adaptive hydrogels that can specifically respond to pathological cues and match the highly ordered tissue regeneration process are significantly on‐demand for effective wound management. Herein, multifunctional marine‐derived gold clusterzyme (AuNCs)‐based self‐adaptive hydrogels with microenvironment triggered release behavior are elaborately fabricated for on‐demand antioxidant, anti‐inflammatory and immunoregulation. The marine mussel‐derived catechol ligands (L‐3,4‐dihydroxyphenylalanine) endow AuNCs with enhanced superoxide dismutase‐mimic activity due to their high affinity to superoxide anion free radical (O2−•) and unique electron transfer mechanism, leading to 100% inhibition of O2−•. Upon uniformly crosslinking with phenylboronic acid‐modified marine‐derived sodium alginate (PBA‐Sa), the obtained AuNCs@PBA‐Sa hydrogels exhibit outstanding self‐healing property, tunable degradation and good removability. Meanwhile, AuNCs can greatly enhance the mechanical property and confer the hydrogel with favorable tissue adhesion for rapid hemostasis. Furthermore, injectable AuNCs@PBA‐Sa hydrogels can not only adapt their shape to the irregular wound, but also smartly adapt their microstructure to the physiological microenvironment of diabetic wound, leading to the responsive release of AuNCs upon the break of boronate ester bonds. The released gold clusterzymes can actively induce the generation of M2‐macrophage, demonstrating an outstanding anti‐inflammatory and pro‐regeneration effect. Therefore, the present multifunctional clusterzyme‐based self‐adaptive hydrogels hold great potential for remolding the dynamic tissue regeneration microenvironment and smart wound management.

Degradable Microneedle Patch with Photothermal-Promoted Bacteria-Infected Wound Healing and Microenvironment Remodeling.

Bacteria-infected wound healing is one of the most challenging issues in health management that is attracting worldwide concerns. Despite great achievements with antibiotics, emergence of antibiotic-resistance retarded the wound healing process and also led to severe outcomes. Exploration of novel antibiotics together with amelioration of wound healing efficacy is desirable. Herein, a degradable microneedle patch (AAZH@MNs) was fabricated through incorporating near-infrared light responsive photothermal agents for sustained bacteria killing and prevention of biofilm formation. In addition, the antibacterial microneedle patch could even remold the microenvironment of bacteria-infected wounds through an antibacterial effect, significantly facilitating the wound healing process.

Bioinspired zwitterionic lysine glycopolymers: Enhancing wound repair through microenvironment modulation for bacterial elimination and optimal immunoregulation

Bacterial infected wounds pose a significant threat to patient survival, necessitating prompt and effective therapeutic intervention. Biomaterials that are responsive to wound microenvironments, possess well-defined structures and are facile to fabricate are favored for fulfilling their mission of efficient wound repair. Drawing inspiration from the immunoregulatory properties of natural zwitterionic capsular polysaccharides (ZPS) and glucomannan (GM) as well as the biogenesis of nitric oxide (NO), this study introduces the zwitterionic lysine glycopolymers (ZLGs), which harmoniously integrate the antibacterial, anti-fouling and immunoregulatory functions into one entity, to effectively promote the healing of infected wounds without addition of any external cytokines or molecular drugs. The ZLGs, exhibiting excellent cytocompatibility, restore sustained NO biogenesis (∼7.1 μM) in wound environment and thus to clean bacteria fast and effectively (12 h clearance rate for S. aureus: 97 %; E. coli: 92 %). Notably, the cell-membrane affinitive ZLGs induce efficient aggregation of mannose receptors and polarize the macrophages to M2 phenotype via the PI3K-Akt/STAT3 pathway, resulting in a synergistic enhanced polarization efficiency increasement of 105 %, as compare to the cumulation of individual building modules. The bioinspired ZLGs accelerate the repair of S. aureus infected wounds in vivo, highlighting the significance of this multi-in-one construction strategy for chronic wound treatment.

Cobalt-phenolic nanoparticles-driven self-assembly of hyaluronic acid hydrogels providing a multifactorial approach for chronic wound management

Chronic wounds are persistent non-healing lesions whose complex management is due to the interplay of multiple factors promoting chronicity, such as oxidative stress, overexpressed enzyme activities impeding the tissue repair and bacterial contamination. Currently marketed chronic wound dressings are designed mainly to absorb wound exudate, and at most to release antimicrobial agents, usually ionic silver. However, an effective wound repair requires addressing the multifactorial nature of the wound in a holistic approach. This study explores the potential of metal phenolic network (MPN) nanoparticles (NPs), comprised of epigallocatechin gallate (EGCG) and cobalt, as active agents and structural elements in wound dressings. The MPN NPs were able to generate reactive oxygen species (ROS), disturb bacterial membrane, and inhibit the biofilm of both gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa. Owing to the high interfacial activity of their phenolic shells, the NPs drove the self-assembly of thiolated hyaluronic acid (THA) hydrogels featuring injectability, self-healing, stimuli-responsive NPs delivery in wound microenvironment, and control over deleterious enzyme activities, oxidative stress and bacterial colonisation. Specifically, the hydrogels inhibited matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) by 60 and 80 %, respectively, and achieved 4-log reduction of S. aureus and 2-log reduction of P. aeruginosa concentrations. Finally, the hydrogels were in-vivo validated in a mouse animal model, showing lack of toxicity and similar wound healing efficiency as an antibiotic-containing commercial product.

Enhancing diabetic wound healing: A two-pronged approach with ROS scavenging and ROS-independent antibacterial properties

The intricate microenvironment often hinders diabetic wounds from following a normal healing process, marked by prolonged low-grade inflammation, thereby slowing or stalling wound healing. Nanomedicine stands as a pivotal branch in the evolution of therapeutic strategies, yet grapples with inherent conflicting traits – the ROS-dependent antibacterial properties of most materials and the anti-inflammatory ROS-scavenging capabilities. This study introduces a multifunctional MOF-199/GO nanocomposite designed to promote diabetic wound healing by its robust ROS scavenging capacity, ROS-independent antibacterial and anti-biofilm properties, and the ability to modulate wound microenvironments. In a skin wound model on type I diabetes rats, the addition of MOF-199/GO efficiently orchestrates the healing process into the defined phases of inflammation, proliferation, and remodeling, achieving a remarkable 96 % wound closure by day 10. When employed as a drug, MOF-199/GO exhibits minimal biological toxicity in vivo. Moreover, when combined with various dressing materials, the drug’s performance remains unchanged, indicating its practical application value.

Hydroxypropyl methylcellulose reinforced bilayer hydrogel dressings containing L-arginine-modified polyoxometalate nanoclusters to promote healing of chronic diabetic wounds

Diabetes-related slow healing of wounds is primarily driven by bacterial infections and angiogenesis disorder and presents a substantial hurdle in clinical treatment. To solve the above problems, an advanced multifunctional hydrogel system based on natural polymer was created here to facilitate wound healing in patients with chronic diabetes. The prepared dressing was composed of an outer hydrogel containing polyvinyl alcohol and hydroxypropyl methyl cellulose in dimethyl sulfoxide and water as binary solvents, and an inner hydrogel containing chitosan quaternary ammonium salt, flaxseed gum, and polyvinyl alcohol. Thus, a polysaccharide based bilayer hydrogel (BH) with superior mechanical strength and biocompatibility was created. This bilayer hydrogel could easily bind to dynamic tissue surfaces, thereby generating a protective barrier. Meanwhile, L-arginine-modified polyoxometalate (POM@L-Arg) nanoclusters were loaded in the inner hydrogel. They released NO when stimulated by the peroxide microenvironment of diabetic wounds. NO as a signal molecule regulated vascular tension and promoted cell proliferation and migration. Additionally, because of the synergistic effect of NO and the chitosan quaternary ammonium salt, the hydrogel system exhibited excellent antibacterial performance. The NO released reduced the levels of proinflammatory factors IL-6 and TNF-α in the diabetic wounds, which thus accelerated wound healing. In short, BH + POM@L-Arg is expected to serve as an ideal wound dressing as it exerts a good promotion effect on diabetes-related wound healing.

Motion-Accommodating Dual-Layer Hydrogel Dressing to Deliver Adipose-Derived Stem Cells to Wounds.

Current dressing materials cannot secure a cell survival-promoting wound environment for stem cell delivery due to insufficient assimilation to skin motion. The authors developed a novel motion-accommodating dual-layer hydrogel dressing for stem cell delivery into such wounds. Dorsal hand skin movement was evaluated to determine the potential range of deformation for a dressing. The outer hydrogel (OH) was fabricated with an alginate-acrylamide double-network hydrogel with a covalently cross-linked elastomer coat. The tough adhesive consisted of a chitosan-based bridging polymer and coupling reagents. OH material properties and adhesiveness on porcine skin were measured. An oxidized alginate-based inner hydrogel (IH) containing human adipose-derived stem cells (ASCs) was evaluated for cell-supporting and cell-releasing properties. The OH's function as a secondary dressing, and dual-layer hydrogel cell delivery potential in wounds were assessed in a rodent model. The dual-layer hydrogel consisted of OH and IH. The OH target range of deformation was up to 25% strain. The OH adhered to porcine skin, and showed significantly higher adhesion energy than common secondary dressings and endured 900 flexion-extension cycles without detachment. OH showed a similar moisture vapor transmission rate as moisture-retentive dressings. IH maintained embedded cell survival for three days with significant cell release on the contacting surface. OH showed less fibrotic wound healing than other secondary dressings in vivo. The dual-layer hydrogel successfully delivered ASCs into open wounds of nude mice (13 ± 3 cells/HPF). The novel dual-layer hydrogel can accommodate patient movement and deliver ASCs into the wound bed by securing the wound microenvironment.

Polyphenol-based photothermal nanoparticles with sprayable capability for self-regulation of microenvironment to accelerate diabetic wound healing

Current treatments for diabetic wounds have some curative effect, but the process is complicated and lack user-friendly wound dressings. Nanozymes have gained significant attention for wound healing due to their striking merits. Herein, we have developed a novel sprayable tannin acid-cobalt coordination nanozyme (TACo) for diabetic wound healing. TACo nanozyme offers a convenient and efficient methods by spraying directly onto wounds surface, reducing infection risk by avoiding direct contact. Notably, its antioxidant properties contribute to scavenging the reactive oxygen species (ROS), alleviating oxidative stress and inflammation of wound microenvironment. Additionally, TACo nanozyme could promote cell survival and multiplication, which is crucial for the wound healing process. Importantly, TACo nanozyme facilitates angiogenesis by enhancing cell viability, migration, and tube formation. The unique coordination between metal and phenolic components confers pH-responsive cobalt ion and TA release properties, avoiding secondary damage during the wound cleaning. This unique composition seamlessly integrates photothermal antibacterial therapy, inflammatory microenvironment management, supporting for angiogenesis, and effective promotion of extracellular matrix production sequentially by harnessing the acidic pH environment of diabetic wounds. In conclusion, the development of a sprayable TACo nanozyme presents a promising therapeutic approach for the treatment of diabetic wounds, addressing the complexities of current treatments and providing a user-friendly application method.

Current Aspects of Nanotechnology Based Healing Approaches for Diabetic Wounds

Abstract: Diabetic wounds represent a significant clinical challenge due to their chronic nature, slow healing rates, and susceptibility to infections, often leading to severe complications. Nanotechnology plays a transforming role in advancing diabetic wound repair therapies. The field of nanotechnology has shown great promise in the medical field in recent years, offering precise tools and materials at the nanoscale to address the complexities of diabetic wound management. The latest breakthroughs in nanomaterial design and fabrication showcase nanoparticles, nanofibers, and hydrogels tailored to enhance tissue regeneration, promote angiogenesis, and modulate the wound microenvironment. These engineered materials serve as versatile systems for the regulated release of cytokines and antimicrobial agents, offering a multifaceted approach to diabetic wound healing. Nanotechnology enables the growth of smart medication delivery technologies with accurate targeting and sustained delivery of medicinal substances right to the location of the wound. Prolonged injuries in hyperglycemic patients are particularly prone to infections, leading to prolonged healing times and increased morbidity. Some of the nanoscale antimicrobial agents, such as nanozyme-chitosan-derived hydrogel, silver nanoparticles, and antimicrobial peptides that exhibit potent bactericidal properties, reduce the risk of infections and associated complications. Nanosensors and advanced imaging techniques enable real-time monitoring of wound healing progress. These tools provide clinicians with valuable insights into tissue viability, inflammation levels, and treatment efficacy, facilitating timely adjustments to therapeutic regimens. This is an inclusive overview of the current state of nanotechnology for the treatment of diabetic wounds, offering insights into the promise and challenges of this innovative approach, by harnessing the unique properties of nanoscale materials and technologies.

CuCo2O4 Nanoflowers with Multiple Enzyme Activities for Treating Bacterium-Infected Wounds via Cuproptosis-like Death.

Nanozyme-driven catalytic therapy provides a promising treatment strategy for bacterial biofilm-infected wounds. However, the single functionality and limited catalytic efficiency of nanozyme-based materials often restrict the effectiveness of wound infection treatment. In this study, CuCo2O4 nanoflowers with multiple enzymatic activities were prepared for antibacterial/antibiofilm treatment by cuproptosis-like death. CuCo2O4 exhibited peroxidase-like (POD-like) and oxidase-like (OXD-like) dual enzyme activities that generated large amounts of •OH and O2•-. Moreover, the glutathione peroxidase-like (GSH-Px-like) activity of CuCo2O4 was able to reduce the overexpression of GSH in the wound microenvironment, enhancing the therapeutic effects of reactive oxygen species (ROS). The morphology of CuCo2O4 was modified using a hydrothermal method with PEG4000 as the solvent, resulting in the exposure of more active center sites and a significant improvement in enzyme catalytic activity. The in vitro results demonstrated the pronounced disruption effect of CuCo2O4 on biofilms formed by bacteria. In vivo, CuCo2O4 significantly promoted angiogenesis, collagen deposition, and cell proliferation. Transcriptome sequencing revealed that elevated ROS levels in bacteria led to cell membrane damage and metabolic disruption. In addition, Cu2+ overload in bacteria induces lipid peroxidation accumulation and disrupts the respiratory chain and tricarboxylic acid (TCA) cycle, ultimately leading to bacterial cuproptosis-like death. This therapeutic strategy, which combines the synergistic effects of multiple enzyme-like activities with cuproptosis-like death, provides an approach for treating biofilm infections.

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.

All-in-one polysaccharide hydrogel with resistant vascular burst pressure and cooperative wound microenvironment regulation for fatal arterial hemorrhage and diabetic wound healing

Fatal massive hemorrhage and diabetic wound healing are world widely challenging in surgical managements, and uncontrolled bleeding, chronic inflammation and damaged remodeling heavily hinder the whole healing processes. Considering hemostasis, inflammation and wound microenvironment cooperatively affect the healing progression, we design all-in-one beta-glucan (BG) hybrid hydrogels reinforced with laponite nanoclay that demonstrate tunable tissue adhesion, resistant vascular burst pressure and cooperative wound microenvironment regulation for arterial hemostasis and diabetic wound prohealing. Those hydrogels had honeycomb-like porous microstructure with average pore size of 7–19 μm, tissue adhesion strength of 18–46 kPa, and vascular burst pressure of 58–174 mmHg to achieve superior hemostasis in rat liver and femoral artery models. They could effectively scavenge reactive oxygen species, transform macrophages from proinflammatory M1 into prohealing M2, and shorten the inflammation duration via synergistic actions of BG and nitric oxide (NO). Single treatment of NO-releasing BG hybrid hydrogels attained complete closure of diabetic wounds within 14 days, orchestrated to accelerate the epithelization and dermis growth, and restored normal vascularization, achieving high performance healing with optimal collagen deposition and hair follicle regeneration. Consequently, this work opens up a new avenue to design all-in-one polysaccharide hydrogels for applications in massive bleeding hemostats and diabetic wound dressings.

Low-level laser activates Wnt/β-catenin signaling pathway-promoting hair follicle stem cell regeneration and wound healing: Upregulate the expression of key downstream gene Lef 1.

The objective of this study is to investigate the mechanism by which low-level laser stimulation promotes the proliferation of intraepithelial hair follicle stem cells (HFSCs) in wounds. This research aims to expand the applications of laser treatment, enhance wound repair methods, and establish a theoretical and experimental foundation for achieving accelerated wound healing. The experimental approach involved irradiating a cell model with low-level laser to assess the proliferation of HFSCs and examine alterations in the expression of proteins related to the Wnt/β-catenin signaling pathway. A mouse back wound model was established to investigate the effects of low-level laser irradiation on wound healing rate, wound microenvironment, and the proliferation of HFSCs in relation to the Wnt/β-catenin signaling pathway. The research findings indicate that low-level laser light effectively activates the Wnt signaling pathway, leading to the increased accumulation of core protein β-catenin and the upregulation of key downstream gene Lef 1. Consequently, this regulatory mechanism facilitates various downstream biological effects, including the notable promotion of HFSC proliferation and differentiation into skin appendages and epithelial tissues. As a result, the process of wound healing is significantly accelerated. Low levels of laser activates the Wnt signalling pathway, promotes the regeneration of hair follicle stem cells and accelerates wound healing.

Topical probiotics in wound care: A review of effects, mechanisms, and applications

Abstract The wound healing process depends on the wound microenvironment, influenced by factors like moisture, pH, bacteria, and immune activity. Current wound care strategies have drawbacks, necessitating safer non-drug–based methods. Recent research highlights the role of skin flora, particularly topical probiotics, in influencing the microenvironment and promoting wound healing. This article provides a comprehensive review of wound care research involving topical probiotics. It summarizes existing types of topical probiotics, their applications for various wound types, administration methods, and healing effects. The biological mechanisms promoting wound healing, such as immunomodulation, antibacterial properties, and growth factor release, are analyzed. Building on this, further exploration is conducted on the application challenges of topical probiotics in the field of wound care. Future prospects and trends are analyzed, and requirements and directions for relevant research design are proposed. This aims to provide valuable insights and guidance for future basic research and clinical practice in the realm of wound care.

Optimizing skin wound healing: The crucial role of the innate immune system and inflammatory microenvironment

Skin, as a part of the innate immune system, represents the first line of defense against pathogens. Each mechanical damage to the skin surface disrupts its homeostasis, thus rapidly inducing the cascade of repair processes. Wound healing comprises 4 subsequent and overlapping steps: hemostasis, inflammation, proliferation, and remodeling. The interplay of the abovementioned phases results in successful cell restoration and tissue repair. The efficiency of wound healing depends on numerous internal and external factors. The proper recruitment of immune cells, such as neutrophils and macrophages, and their interactions with keratinocytes, fibroblasts, and extracellular matrix (ECM) accounts for one of the most significant elements affecting this process. Despite the interaction of the immune cells, the development of a highly favorable microenvironment surrounding the damaged area also constitutes a vital component of successful healing. These optimal conditions combined with the inflow of stimuli, such as cytokines and growth factors, lead to complete wound closure and skin surface restoration. Nevertheless, in order to increase the efficiency of wound healing treatment and improve existing technologies, it is essential to gain a deeper understanding of the healing steps’ complexity. In this work, we elucidated basic mechanisms regarding skin injury sealing with a focus on the creation of a highly beneficial inflammatory microenvironment. The presented paper outlines current approaches to managing the excessive inflammation of the skin wound microenvironment to improve the treatment of chronic wounds. The most important perspectives in immunology phase modulation include the use of pharmaceuticals, natural bioactive compounds, immunomodulatory scaffolds, skin substitutes, cell-based therapies, and growth factors or cytokines injections.

Self-healing hydrogel prepared from gallic acid coupled P(NIPAM-co-AH) and oxidized sodium alginate for diabetic wound repairing

Due to the complex wound microenvironment, diabetic wound repairing remains as an important clinical problem caused by excessive ROS, bacterial infection and persistent inflammation. In this study, gallic acid (GA) was grafted onto the P(NIPAM-co-AH) copolymers to synthesize functional copolymer with hydrazide functional group and GA moiety (PNHG). Then the PNHG was cross-linked by sodium alginate oxide (OSA) to fabricate self-healing hydrogel with multifunctionalility of tissue adhesion, ROS scavenging, biodegradability and antibacterial property. The multifunctional hydrogel showed expected advantages proved the GA enhanced the ROS scavenging property, tissue adhesion and antibacterial activity. Moreover, the hydrogel preserved the biocompatibility and the biodegradability of the precursors. Furthermore, the multifunctional hydrogel showed improved hemostatic property and greatly promoted repairing rate of diabetic wounds on mice model in vivo. In conclusion, this multifunctional PNHG/OSA hydrogel can play a important role as wound dressing in the future.

NIR‐Responsive Multifunctional Artificial Skin for Regenerative Wound Healing

AbstractEfficient wound repair with skin appendage regeneration following severe trauma poses a challenge due to the scarcity of skin grafts and decreased drug effectiveness in protease‐rich wound microenvironments. Here, a multifunctional artificial skin (NIR‐mFAS) with photothermal‐triggered drug delivery capabilities is designed to actively and comprehensively improve the regenerative potential of full‐thickness wounds. The antibacterial chitosan/silk fibroin hydrogel matrix of artificial skin, cross‐linked by electrostatic interactions, effectively encapsulates and sustains the release of epidermal growth factor (EGF) to accelerate re‐epithelialization and neovascularization by promoting the migration and proliferation of repair cells. Subsequently, the photothermal responsive polydopamine nanoparticles (PDA‐NPs) dispersed in the matrix enable precise control over the release of BMP4 under the irradiation of 1064 nm NIR, thereby inhibiting scarring by reducing myofibroblasts during the proliferative stage. Importantly, the concurrent controlled release of CHIR99021 can modulate cell fate by inducing the conversion of myofibroblasts into dermal papilla‐like cells, leading to hair follicle and sebaceous gland regeneration. The NIR‐mFAS functions as an advanced delivery system for achieving high‐quality wound healing with appendage regeneration and offers a smart therapeutic approach that can be applied to other treatments requiring coordinated delivery of multiple pharmacological agents.

Microenvironment-triggered cascade metal-polyphenolic nanozyme for ROS/NO synergistic hyperglycemic wound healing

Wound infection of hyperglycemic patient often has extended healing period and increased probability due to the high glucose level. However, achieving precise and safe therapy of the hyperglycemic wound with specific wound microenvironment (WME) remains a major challenge. Herein, a WME-activated smart L-Arg/GOx@TA-Fe (LGTF) nanozymatic system composed of generally recognized as safe (GRAS) compound is engineered. The nanozymatic system combining metal-polyphenol nanozyme (tannic acid-Fe3+, TA-Fe) and natural enzyme (glucose oxidase, GOx) can consume the high-concentration glucose, generating reactive oxygen species (ROS) and nitric oxide (NO) in situ to synergistically disinfect hyperglycemia wound. In addition, glucose consumption and gluconic acid generation can lower glucose level to promote wound healing and reduce the pH of WME to enhance the catalytic activities of the LGTF nanozymatic system. Thereby, low-dose LGTF can perform remarkable synergistic disinfection and healing effect towards hyperglycemic wound. The superior biosafety, high catalytic antibacterial and beneficial WME regulating capacity demonstrate this benign GRAS nanozymatic system is a promising therapeutic agent for hyperglycemic wound.