Clinical treatment of diabetic refractory ulcers is impeded by chronic inflammation and cell dysfunction associated with wound healing. The significant clinical application of bFGF in wound healing is limited by its instability in vivo. Sulfur has been applied for the treatment of skin diseases in the clinic for antibiosis. We previously found that sulfur incorporation improves the ability of selenium nanoparticles to accelerate wound healing, yet the toxicity of selenium still poses a risk for its clinical application. To obtain materials with high pro-regeneration activity and low toxicity, we explored the mechanism by which selenium-sulfur nanoparticles aid in wound healing via RNA-Seq and designed a nanoparticle called Nano-S@bFGF, which was constructed from sulfur and bFGF. As expected, Nano-S@bFGF not only regenerated zebrafish tail fins and promoted skin wound healing but also promoted skin repair in diabetic mice with a profitable safety profile. Mechanistically, Nano-S@bFGF successfully coactivated the FGFR and Hippo signalling pathways to regulate wound healing. Briefly, the Nano-S@bFGF reported here provides an efficient and feasible method for the synthesis of bioactive nanosulfur and bFGF. In the long term, our results reinvigorated efforts to discover more peculiar unique biofunctions of sulfur and bFGF in a great variety of human diseases.

The treatment of diabetic wounds possessed significant challenges in clinical practice, which was accompanied with continuous infection, inflammation, and limited angiogenesis. Current wound dressings used for diabetic wound healing struggle to address these issues simultaneously. Therefore, Ga3+ was added to the chitosan/silk solution to confer potent antibacterial properties. Subsequently, umbilical cord mesenchymal stem cell exosomes (UCSC-Exo) were integrated into the gallium/chitosan/silk solution to enhance its angiogenesis-inducing activity. The mixture was lyophilized to prepare gallium/chitosan/silk/exosome sponge scaffolds (Ga/CSSF-Exo sponge scaffolds). The experiments of In vitro and in vivo demonstrated that Ga/CSSF-Exo sponge scaffolds exhibited sustained release of Ga3+ and bioactive exosomes, which effectively exerted continuous antibacterial effects and promoted angiogenesis. In diabetic rat wound models, Ga/CSSF-Exo sponge scaffolds facilitated angiogenesis, suppressed bacterial growth and inflammation, as well as promoted collagen deposition and re-epithelialization of wounds. Collectively, our findings suggested that Ga/CSSF-Exo held excellent potential for diabetic wound healing.

UNASSIGNED: This research was to innovate a nanozyme-based therapeutic strategy that combines aggregation-induced emission (AIE) photosensitizers with copper nanozymes. This approach is designed to address the hypoxic conditions often found in bacterial infections and aims to boost the effectiveness of photodynamic therapy (PDT) by ensuring sufficient oxygen supply for reactive oxygen species (ROS) generation.
UNASSIGNED: Our approach involved the synthesis of dihydroxyl triphenyl vinyl pyridine (DHTPY)-Cu@zoledronic acid (ZOL) nanozyme particles. We initially synthesized DHTPY and then combined it with copper nanozymes to form the DHTPY-Cu@ZOL composite. The nanozyme\'s size, morphology, and chemical properties were characterized using various techniques, including dynamic light scattering, transmission electron microscopy, and X-ray photoelectron spectroscopy. We conducted a series of in vitro and in vivo tests to evaluate the photodynamic, antibacterial, and wound-healing properties of the DHTPY-Cu@ZOL nanozymes, including their oxygen-generation capacity, ROS production, and antibacterial efficacy against methicillin-resistant Staphylococcus aureus (MRSA).
UNASSIGNED: The DHTPY-Cu@ZOL exhibited proficient H2O2 scavenging and oxygen generation, crucial for enhancing PDT in oxygen-deprived infection environments. Our in vitro analysis revealed a notable antibacterial effect against MRSA, suggesting the nanozymes\' potential to disrupt bacterial cell membranes. Further, in vivo studies using a diabetic rat model with MRSA-infected wounds showed that DHTPY-Cu@ZOL markedly improved wound healing and reduced bacterial presence, underscoring its efficacy as a non-antibiotic approach for chronic infections.
UNASSIGNED: Our study suggests that DHTPY-Cu@ZOL is a highly promising approach for combating antibiotic-resistant microbial pathogens and biofilms. The biocompatibility and stability of these nanozyme particles, coupled with their improved PDT efficacy position them as a promising candidate for clinical applications.

The utilization of platelet-rich plasma (PRP) has exhibited potential as a therapeutic approach for the management of diabetic foot ulcers (DFUs). However, it is currently not well understood how the diabetic environment may influence PRP-derived exosomes (PRP-Exos) and their potential impact on neutrophil extracellular traps (NETs). This study aims to investigate the effects of the diabetic environment on PRP-Exos, their communication with neutrophils, and the subsequent influence on NETs and wound healing. Through bulk-seq and Western blotting, we confirmed the increased expression of MMP-8 in DFUs. Additionally, we discovered that miRNA-26b-5p plays a significant role in the communication between DFUs and PRP-Exos. In our experiments, we found that PRP-Exos miR-26b-5p effectively improved diabetic wound healing by inhibiting NETs. Further tests validated the inhibitory effect of miR-26b-5p on NETs by targeting MMP-8. Both in vitro and in vivo experiments showed that miRNA-26b-5p from PRP-Exos promoted wound healing by reducing neutrophil infiltration through its targeting of MMP-8. This study establishes the importance of miR-26b-5p in the communication between DFUs and PRP-Exos, disrupting NETs formation in diabetic wounds by targeting MMP-8. These findings provide valuable insights for developing novel therapeutic strategies to enhance wound healing in individuals suffering from DFUs.

Healing of chronic diabetic wounds is challenging due to complications of severe inflammatory microenvironment, bacterial infection and poor vascular formation. Herein, a novel injectable polyvinyl alcohol-hyaluronic acid-based composite hydrogel was developed, with tannic acid (TA) and silicate functionalization to fabricate an \'all-in-one\' hydrogel PTKH. On one hand, after being locally injected into the wound site, the hydrogel underwent a gradual sol-gel transition in situ, forming an adhesive and protective dressing for the wound. Manipulations of rheological characteristics, mechanical properties and swelling ability of PTKH could be performed via regulating TA and silicate content in hydrogel. On the other hand, PTKH was capable of eliminating reactive oxygen species overexpression, combating infection and generating a cell-favored microenvironment for wound healing acceleration in vitro. Subsequent animal studies demonstrated that PTKH could greatly stimulate angiogenesis and epithelization, accompanied with inflammation and infection risk reduction. Therefore, in consideration of its impressive in vitro and in vivo outcomes, this \'all-in-one\' multifunctional hydrogel may hold promise for chronic diabetic wound treatment.

The development of a multifunctional wound dressing that can adapt to the shape of wounds and provide controlled drug release is crucial for diabetic patients. This study developed a carboxymethyl chitosan-based hydrogel dressing with enhanced mechanical properties and tissue adherence that were achieved by incorporating pectin (PE) and polydopamine (PDA) and loading the hydrogel with recombinant human epidermal growth factor (rhEGF). This EGF@PDA-CMCS-PE hydrogel demonstrated robust tissue adhesion, enhanced mechanical properties, and superior water retention and vapor permeability. It also exhibited significant antioxidant capacity. The results showed that EGF@PDA-CMCS-PE could effectively scavenge 2,2\'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate)， (1,1-diphenyl-2-picrylhydrazyl), and superoxide anions and increase superoxide dismutase and catalase levels in vivo. In vitro cytotoxicity and antibacterial assays showed good biocompatibility and antimicrobial properties. The sustained release of EGF by the hydrogel was confirmed, with a gradual release profile over 120 h. In vivo studies in diabetic mice showed that the hydrogel significantly accelerated wound healing, with a wound contraction rate of 97.84% by day 14. Histopathological analysis revealed that the hydrogel promoted fibroblast proliferation, neovascularization, and orderly connective tissue formation, leading to a more uniform and compact wound-healing process. Thus, EGF@PDA-CMCS-PE hydrogel presents a promising tool for managing chronic diabetic wounds, offering a valuable strategy for future clinical applications.

Impaired wound healing in diabetes results from a complex interplay of factors that disrupt epithelialization and wound closure. MG53, a tripartite motif (TRIM) family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) were transduced with lentiviral vectors overexpressing MG53 to investigate their efficacy in diabetic wound healing. Using a db/db mouse wound model, we observed that BMSCs-MG53 significantly enhanced diabetic wound healing. This improvement was associated with marked increase in re-epithelialization and vascularization. BMSCs-MG53 promoted recruitment and survival of BMSCs, as evidenced by an increase in MG53/Ki67-positive BMSCs and their improved response to scratch wounding. The combination therapy also promoted angiogenesis in diabetic wound tissues by upregulating the expression of angiogenic growth factors. MG53 overexpression accelerated the differentiation of BMSCs into endothelial cells, manifested as the formation of mature vascular network structure and a remarkable increase in DiI-Ac-LDL uptake. Our mechanistic investigation revealed that MG53 binds to caveolin-3 (CAV3) and subsequently increases phosphorylation of eNOS, thereby activating eNOS/NO signaling. Notably, CAV3 knockdown reversed the promoting effects of MG53 on BMSCs endothelial differentiation. Overall, our findings support the notion that MG53 binds to CAV3, activates eNOS/NO signaling pathway, and accelerates the therapeutic effect of BMSCs in the context of diabetic wound healing. These insights hold promise for the development of innovative strategies for treating diabetic-related impairments in wound healing.

Multidrug-resistant (MDR) bacteria-infected wound healing remains greatly challenging, especially in diabetic patients. Herein, a novel nano-drug delivery based on endogenous glucose-driven cascade reaction is proposed for boosting MDR bacteria-infected diabetic wound healing with high efficacy by improving wound microenvironment and enhancing photodynamic antibacterial activity. The composite nanoagent is first self-assembled by integrating berberine (BBR) and epigallocatechin gallate (EGCG) from natural plant extracts, named as BENPs, which is successively coated with manganese dioxide nanoshells (MnO2 NSs) and glucose oxidase (GOX) to form the final BEMGNPs. The cascade reaction is triggered by glucose at the wound site of diabetes which is specifically catalyzed by GOX in the BEMGNPs to produce gluconic acid and hydrogen peroxide (H2O2). That is subsequently to decompose MnO2 NSs in the BEMGNPs to generate oxygen (O2). The BEMGNPs as photosensitizers effectively produce reactive oxygen species (ROS) to enhance the eradication of bacteria with the assistance of O2. Under the synergistic function of the cascaded reaction, the BEMGNPs present excellent antibacterial efficacy even for MDR bacteria. The in vivo experiments explicitly validate that the constructed nano-drug delivery can augment the MDR bacteria-infected diabetic wound healing with excellent biosafety. The as-proposed strategy provides an instructive way to combat ever-threatening MDR bacteria, which particularly is beneficial for diabetic patients.

Keratinocyte and fibroblast dysfunctions contribute to delayed healing of diabetic wounds. Small extracellular vesicles (sEV) are key mediators of intercellular communication and are involved in the pathogenesis of several diseases. Recent findings suggest that sEV derived from high-glucose-treated keratinocyte (HaCaT-HG-sEV) can transport LINC01435 to inhibit tube formation and migration of HUVECs, thereby delaying wound healing. This study aimed to elucidate sEV-related communication mechanisms between keratinocytes and fibroblasts during diabetic wound healing. HaCaT-HG-sEV treatment and LINC01435 overexpression significantly decreased fibroblast collagen level and migration ability but significantly increased fibroblast autophagy. However, treatment with an autophagy inhibitor suppressed LINC01435 overexpression-induced decrease in collagen levels in fibroblasts. In diabetic mice, HaCaT-HG-sEV treatment decreased collagen levels and increased the expression of the autophagy-related proteins Beclin-1 and LC3 at the wound site, thereby delaying wound healing. Conclusively, LINC01435 in keratinocyte-derived sEV activates fibroblast autophagy and reduces fibroblast collagen synthesis, leading to impaired diabetic wound healing.
Diabetic foot ulcers are a serious complication of diabetes and can lead to amputation and death. Therefore, it is crucial to comprehensively elucidate the mechanisms of delayed diabetic wound healing, with emphasis on the role of keratinocyte-derived small extracellular vesicles. In vivo and in vitro experiments showed that keratinocyte-derived small extracellular vesicles suppressed diabetic wound healing, which is partly attributed to the effects of their content (LINC01435) in fibroblasts. This study suggests that LINC01435 could be targeted to regulate diabetic wound healing.

Diabetic wounds, characterized by prolonged inflammation and impaired vascularization, are a serious complication of diabetes. This study aimed to design a gelatin methacrylate (GelMA) hydrogel for the sustained release of netrin-1 and evaluate its potential as a scaffold to promote diabetic wound healing. The results showed that netrin-1 was highly expressed during the inflammation and proliferation phases of normal wounds, whereas it synchronously exhibited aberrantly low expression in diabetic wounds. Neutralization of netrin-1 inhibited normal wound healing, and the topical application of netrin-1 accelerated diabetic wound healing. Mechanistic studies demonstrated that netrin-1 regulated macrophage heterogeneity via the A2bR/STAT/PPARγ signaling pathway and promoted the function of endothelial cells, thus accelerating diabetic wound healing. These data suggest that netrin-1 is a potential therapeutic target for diabetic wounds.