Multifunctional nanofibrous membranes enhance diabetic wound healing by inhibiting endothelial pyroptosis and regulating macrophage polarization

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 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.