Anti-apoptotic effects of ruthenium nanozyme-augmented adipose stem cells accelerate cutaneous wound healing.

Background Persistent oxidative stress and aberrant inflammatory responses are major contributors to delayed wound healing in diabetic patients. Endothelial cell pyroptosis, a form of inflammatory programmed cell death, plays a critical role in vascular dysfunction and impaired tissue regeneration in diabetic wounds. Targeting endothelial pyroptosis therefore represents a promising therapeutic strategy. This study aims to develop a multifunctional nanofibrous scaffold capable of suppressing oxidative stress–induced endothelial pyroptosis while modulating the inflammatory microenvironment to promote angiogenesis and diabetic wound repair. Methods In this study, a pH-responsive nanoplatform based on zinc–imidazolate metal–organic frameworks (ZIF-8) was constructed for the controlled delivery of luteolin (Lut), a natural flavonoid with anti-inflammatory and antioxidant properties. The physicochemical characteristics, drug-loading efficiency, and pH-responsive release behavior of Lut@ZIF-8 nanoparticles were systematically evaluated. The effects of Lut@ZIF-8 on oxidative stress, endothelial pyroptosis, and angiogenic function were investigated in vitro, while therapeutic efficacy was further assessed in a diabetic mouse wound model using Lut@ZIF-8-loaded fibrous scaffolds. Results Lut@ZIF-8 nanoparticles exhibited uniform morphology, high drug-loading efficiency, and sustained drug release under mildly acidic conditions mimicking the diabetic wound microenvironment. In vitro, Lut@ZIF-8 effectively suppressed reactive oxygen species (ROS) accumulation and inhibited endothelial cell pyroptosis by downregulating the activation of NLRP3 inflammasome components, including caspase-1 and GSDMD, thereby preserving endothelial barrier integrity and angiogenic capacity. In vivo, Lut@ZIF-8-loaded scaffolds significantly reduced inflammatory cytokine expression, enhanced collagen deposition, promoted neovascularization and re-epithelialization, and ultimately accelerated wound closure in diabetic mice. Conclusions The pH-responsive Lut@ZIF-8 nanoplatform effectively modulates oxidative stress and endothelial cell pyroptosis in diabetic wounds, thereby promoting angiogenesis and tissue regeneration. This strategy provides a promising and innovative therapeutic approach for the treatment of chronic diabetic wounds.

Diabetic wounds remain a formidable clinical challenge due to excessive reactive oxygen species (ROS) accumulation, impaired immune regulation, and compromised tissue regeneration. Herein, we report a multifunctional thermosensitive smart hydrogel integrating hollow mesoporous MnO2 nanozymes and transforming growth factor-β1 (TGF-β1) into an adhesive thermosensitive hydrogel (TGF-β1@MATH) for synergistic diabetic wound therapy. The MnO2 nanozymes efficiently scavenge ROS in the diabetic wound microenvironment, suppressing the Nrf2-HO-1-NQO-1 pathway to alleviate oxidative stress and restore the cell migration capacity. Triggered by body temperature, TGF-β1@MATH undergoes stiffness enhancement and controlled TGF-β1 release: the increased stiffness upregulates integrin β2 (ITGB2) expression in T cells, while TGF-β1 synergizes with ITGB2 to activate the Smad2/3 pathway, promoting regulatory T cell (Tregs) aggregation and secretion of growth factors. In vitro studies confirm that TGF-β1@MATH accelerates fibroblast migration, induces myofibroblast differentiation, and modulates the immune microenvironment. In diabetic mice, TGF-β1@MATH achieves a 95% wound healing rate within 14 days, significantly enhancing re-epithelialization, collagen deposition, angiogenesis, and Tregs recruitment. This integrated design addresses multiple pathological barriers of diabetic wound areas (WA) through ROS scavenging, thermosensitive regulation and immune-modulated regeneration, offering a promising translational strategy for clinical diabetic wound management.

A nanofibrous membrane loaded with doxycycline and printed with conductive hydrogel strips promotes diabetic wound healing in vivo

Aucubin-loaded BSAMA/GelMA hydrogel accelerates diabetic wound healing via ROS scavenging.

Dual functional electrospun nanofiber membrane with ROS scavenging and revascularization ability for diabetic wound healing

In diabetic patients with skin injuries, bacterial proliferation, accumulation of reactive oxygen species (ROS) in the tissues, and impaired angiogenesis make wound healing difficult. Therefore, eliminating bacteria, removing ROS, and promoting angiogenesis are necessary for treating acute diabetic wounds. In this study, benefiting from the ability of polyphenols to form a metal-phenolic network (MPN) with metal ions, TA-Eu MPN nanoparticles (TM NPs) were synthesized. The prepared photothermal agent CuS NPs and TM NPs were then loaded onto the supporting base and needle tips of PVA/HA (PH) microneedles, respectively, to obtain PH/CuS/TM microneedles. Antibacterial experiments showed that microneedles loaded with CuS NPs could remove bacteria by the photothermal effect. In vitro experiments showed that the microneedles could effectively scavenge ROS, inhibit macrophage polarization to the M1 type, and induce polarization to the M2 type as well as have the ability to promote vascular endothelial cell migration and angiogenesis. Furthermore, in vivo experiments showed that PH/CuS/TM microneedles accelerated wound healing by inhibiting pro-inflammatory cytokines and promoting angiogenesis in a diabetic rat wound model. Therefore, PH/CuS/TM microneedles have efficient antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, and angiogenic abilities and hold promise as wound dressings for treating acute diabetic wounds.

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Facile strategy for gelatin-based hydrogel with multifunctionalities to remodel wound microenvironment and accelerate healing of acute and diabetic wounds

Impaired wound healing in diabetes is a well-documented phenomenon. Emerging data favor the involvement of free radicals in the pathogenesis of diabetic wound healing. We investigated the beneficial role of the sustained release of reactive oxygen species (ROS) in diabetic dermal wound healing. In order to achieve the sustained delivery of ROS in the wound bed, we have incorporated glucose oxidase in the collagen matrix (GOIC), which is applied to the healing diabetic wound. Our in vitro proteolysis studies on incorporated GOIC show increased stability against the proteases in the collagen matrix. In this study, GOIC film and collagen film (CF) are used as dressing material on the wound of streptozotocin-induced diabetic rats. A significant increase in ROS (p < 0.05) was observed in the fibroblast of GOIC group during the inflammation period compared to the CF and control groups. This elevated level up regulated the antioxidant status in the granulation tissue and improved cellular proliferation in the GOIC group. Interestingly, our biochemical parameters nitric oxide, hydroxyproline, uronic acid, protein, and DNA content in the healing wound showed that there is an increase in proliferation of cells in GOIC when compared to the control and CF groups. In addition, evidence from wound contraction and histology reveals faster healing in the GOIC group. Our observations document that GOIC matrices could be effectively used for diabetic wound healing therapy.

Chronic diabetic wound patients usually show high glucose levels and systemic immune disorder, resulting in high reactive oxygen species (ROS) levels and immune cell dysfunction, prolonged inflammation, and delayed wound healing. Herein, we prepared an antioxidant and immunomodulatory polymer vesicle for diabetic wound treatment. This vesicle is self-assembled from poly(ε-caprolactone)36-block-poly[lysine4-stat-(lysine-mannose)22-stat-tyrosine)16] ([PCL36-b-P[Lys4-stat-(Lys-Man)22-stat-Tyr16]). Polytyrosine is an antioxidant polypeptide that can scavenge ROS. d-Mannose was introduced to afford immunomodulatory functions by promoting macrophage transformation and Treg cell activation through inhibitory cytokines. The mice treated with polymer vesicles showed 23.7% higher Treg cell levels and a 91.3% higher M2/M1 ratio than those treated with PBS. Animal tests confirmed this vesicle accelerated healing and achieved complete healing of S. aureus-infected diabetic wounds within 8 days. Overall, this is the first antioxidant and immunomodulatory vesicle for diabetic wound healing by scavenging ROS and regulating immune homeostasis, opening new avenues for effective diabetic wound healing.

Facile formation of injectable quaternized chitosan/tannic acid hydrogels with antibacterial and ROS scavenging capabilities for diabetic wound healing

Infected diabetic wounds represent a significant challenge in clinical care due to persistent inflammation and impaired healing. To address these issues, the development of novel wound dressings with both antibacterial and reactive oxygen species (ROS) scavenging properties is essential. Herein, we prepare a novel wound dressing composed of Cu2-xO nanoparticles decorated on Ti3C2 MXene (Cu2-xO@Ti3C2) and integrate it into a poly(vinyl alcohol) (PVA) matrix to form electrospun nanofibers (Cu2-xO@Ti3C2@PVA). Cu2-xO@Ti3C2 exhibits remarkable photothermal conversion efficiency and effective ROS scavenging properties. In vitro experiments demonstrated that Cu2-xO@Ti3C2 effectively kills bacteria upon near-infrared (NIR) irradiation, which can be attributed to the photothermal therapy (PTT) effect of Ti3C2. At the same time, the ROS scavenging abilities of both Ti3C2 and Cu2-xO endow Cu2-xO@Ti3C2 with significant in vitro anti-inflammatory effects. As a promising wound dressing, in vivo studies validated the high efficacy of Cu2-xO@Ti3C2@PVA in promoting hemostasis, exerting antibacterial activity, reducing inflammation, and accelerating the healing process of diabetic wounds. This innovative approach provides a comprehensive solution to the multifaceted challenges of diabetic wound healing and paves the way for improved clinical outcomes.

Diabetic wound healing is often impaired due to the high-glucose microenvironment in patients. Among the relevant factors, bacterial infection and overproduction of reactive oxygen species (ROS) have critical roles, and sustained oxidative stress further impairs angiogenesis and increases apoptosis, thereby hindering wound repair. To reduce these effects, we aimed to develop an injectable temperature-sensitive cellulose hydrogel exhibiting anti-apoptotic, oxidative stress-attenuating, antimicrobial, and multi-species enzymatic activities. By simulating the dual active sites of natural copper-zinc superoxide dismutase (CuZn-SOD), a bimetallic mimetic nanoenzyme [Cu/Zn-metal-organic framework (MOF)] was synthesized. Subsequently, Cu/Zn-MOF was incorporated into a hydroxypropyl methylcellulose hydrogel, and the gelation temperature was adjusted to enable a sol-to-gel transition near physiological temperature. A rheometer was used to measure the gelation temperature, and scanning electron microscopy was performed to characterize the surface morphology. The hydrogels were evaluated for multiple enzyme-like activities, including those of SOD, glutathione peroxidase (GPx), thiol peroxidase (TPx), and ascorbate peroxidase (APx). Mouse fibroblasts (L929 cells) and human umbilical vein endothelial cells were used to assess antioxidant, pro-migratory, pro-angiogenic, and anti-apoptotic properties. Antimicrobial activity was assessed against Escherichia coli and Staphylococcus aureus. Western blotting was performed to verify potential anti-inflammatory mechanisms. Finally, wound and infected-wound models were established in diabetic mice to evaluate the hydrogel's effects on wound repair. The hydrogel exhibited a sol-to-gel transition at 37°C and demonstrated favorable injectability and hydrophilicity, providing a moist healing environment. The Cu/Zn-MOF nanoenzymes demonstrated four enzyme-like activities (SOD, GPx, TPx, and APx), enabling cascade ROS scavenging, which was further confirmed in cellular experiments. The Cu/Zn-MOF nanoenzymes also modulated Sirt1/nuclear factor-κ beta expression to influence inflammatory factor release, thereby exhibiting strong anti-inflammatory activity. The hydrogel also exerted cell migration, angiogenesis, and anti-apoptotic effects. Antimicrobial assays showed kill rates of 99.39% and 99.67% against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively. In a diabetic mouse wound model, the hydrogel significantly enhanced pro-healing effects by promoting neovascularization and collagen deposition through ROS and bacterial clearance, thereby reducing the inflammatory response. Biomimetic nanoenzymes were synthesized and incorporated into temperature-sensitive injectable hydrogels, which exhibited strong antioxidant and antimicrobial activities that have considerable potential for diabetic wound therapy.

The content of heparan sulphate is reduced in the endothelium under hyperglycaemic conditions and may contribute to the pathogenesis of atherosclerosis. Heparanase-1 (HPR1) specifically degrades heparan sulphate proteoglycans. We therefore sought to determine whether: (1) heparan sulphate reduction in endothelial cells is due to increased HPR1 production through increased reactive oxygen species (ROS) production; and (2) HPR1 production is increased in vivo in endothelial cells under hyperglycaemic and/or atherosclerotic conditions. HPR1 mRNA and protein levels in endothelial cells were analysed by RT-PCR and Western blot or HPR1 enzymatic activity assay, respectively. Cell surface heparan sulphate levels were analysed by FACS. HPR1 in the artery from control rats and a rat model of diabetes, and from patients under hyperglycaemic and/or atherosclerotic conditions was immunohistochemically examined. High-glucose-induced HPR1 production and heparan sulphate degradation in three human endothelial cell lines, both of which were blocked by ROS scavengers, glutathione and N-acetylcysteine. Exogenous H(2)O(2) induced HPR1 production, subsequently leading to decreased cell surface heparan sulphate levels. HPR1 content was significantly increased in endothelial cells in the arterial walls of a rat model of diabetes. Clinical studies revealed that HPR1 production was increased in endothelial cells under hyperglycaemic conditions, and in endothelial cells and macrophages in atherosclerotic lesions. Hyperglycaemia induces HPR1 production and heparan sulphate degradation in endothelial cells through ROS. HPR1 production is increased in endothelial cells from a rat model of diabetes, and in macrophages in the atherosclerotic lesions of diabetic and non-diabetic patients. Increased HPR1 production may contribute to the pathogenesis and progression of atherosclerosis.

Bioactive substance-integrated hydrogels have demonstrated efficacy in diabetic wound treatment. However, challenges remain in identifying naturally derived, multifunctional active substances capable of addressing the complex pathophysiology of wounds, as well as in tailoring hydrogels to enhance their suitability for wound applications. Here, we present a novel biological hydrogel microcarrier system by integrating Bletilla striata-derived nanoparticles (PdNPs) and polydopamine nanozymes (PDAs) into a hyaluronic acid-methacrylate (HAMA) hydrogel. PdNPs can polarize over-activated macrophages to an anti-inflammatory phenotype and restore fibroblast functionality. Meanwhile, PDAs act as potent reactive oxygen species (ROS) scavengers and protect fibroblasts from oxidative stress-induced apoptosis. When encapsulated into HAMA microcarriers, the PdNP + PDA@HAMA microcarriers significantly accelerate wound healing in a diabetic rat model. These outcomes demonstrate the therapeutic potential of our natural, multifunctional hydrogel microcarriers as a promising wound dressing platform for the treatment of chronic diabetic wounds.