A BAI1-PSTB-Hydrogel promotes diabetic wound healing by targeting mtDNA leakage and the cGAS-STING axis to alleviate endothelial senescence.

Abstract

Diabetic Wound (DW) is one of the most prevalent complications in diabetes patients, impairing patient wellbeing and quality of life severely. The pathogenesis of DW remains incompletely understood, hindering the development of targeted therapies. We analyzed single-cell RNA sequencing data and tissue samples from DW patients and healthy controls to investigate characteristic of DW. A high-glucose (30 mM) stimulation model was used to mimic Vascular endothelial cells （VECs) injury in vitro. We evaluated the effects of BAI1 on high-glucose-induced VECs dysfunction, cellular senescence, mitochondrial DNA (mtDNA) leakage, and cGAS-STING pathway activation. To enable topical wound delivery, BAI1 was loaded into mesoporous silica nanoparticles and encapsulated within a polyvinyl alcohol-alginate-tannic acid-borax composite hydrogel. A diabetic mouse wound model was established to assess the therapeutic efficacy of the BAI1-loaded hydrogel. Single-cell sequencing and histopathological analyses revealed severe VECs injury in diabetic wounds, accompanied by STING activation and cellular senescence. In vitro, high glucose induced mtDNA leakage, cGAS-STING activation, and senescence in VECs. BAI1 treatment attenuated mtDNA leakage, suppressed STING activation, reduced senescence, and restored VECs function. The BAI1-loaded hydrogel significantly accelerated wound closure and improved healing quality in diabetic mice. Tissue analysis further demonstrated that the hydrogel reduced STING activation and senescence markers in wounds. mtDNA leakage in VECs drive cellular senescence and contribute to impaired healing in diabetic wounds. BAI1 alleviates senescence by inhibiting BAX, thereby reducing mtDNA release and subsequent cGAS-STING activation. The BAI1-PSTB-Hydrogel is a promising topical dressing for DW, with broad clinical translation potential.