Dual-Network QSAZ@VPH hydrogel-mediated verapamil treatment improved recovery of diabetic ulcer through inhibiting mitochondrial oxidative stress and enhancing angiogenesis

This graphical abstract illustrates a dual-network hydrogel (QSAZ@VPH) delivering verapamil to diabetic wounds. The system targets SRC/calcium signaling pathways, alleviates mitochondrial dysfunction by reducing ROS and apoptosis, and enhances angiogenesis in db/db mice and full-thickness diabetic rat models, thereby accelerating wound healing through endothelial cell activation and matrix remodeling • QSAZ@VPH hydrogel for local verapamil delivery to target mitochondrial dysfunction and promote tissue regeneration in chronic diabetic ulcers. • In vitro demonstration of QSAZ@VPH’s anti-inflammatory, anti-apoptotic, and pro-angiogenic effects on HUVECs under oxidative stress. • Validated therapeutic efficacy in vivo using db/db mice and STZ-induced diabetic rat models, showing QSAZ@VPH accelerated wound healing. • Identified mechanism involving QSAZ@VPH activating the Proto-oncogene tyrosine-protein kinase Src (SRC)/PI3K/AKT pathway to rescue mitochondrial dysfunction. • Addressed challenges in DUs complexity and clinical translation, highlighting QSAZ@VPH as a promising therapeutic strategy. Diabetic ulcer (DU) are severe complications of diabetes, characterized by persistent inflammation, oxidative stress, and impaired mitochondrial function. Verapamil, a calcium channel blocker, has shown potential in reducing oxidative stress and improving mitochondrial dysfunction, but its application in DU treatment remains unexplored. A dual-network QSAZ@VPH hydrogel was developed for local delivery and controlled release of verapamil. In vitro experiments evaluated its protective effects on HUVECs exposed to H 2 O 2 -induced mitochondrial dysfunction, including inflammatory marker expression, apoptosis inhibition, and angiogenesis promotion. In vivo studies used db/db mice and DU model rats to assess wound healing, granulation tissue formation, and neovascularization. In vitro , QSAZ@VPH reduced mitochondrial dysfunction, lowered inflammatory markers, inhibited apoptosis, and promoted angiogenesis. In vivo , the hydrogel significantly improved wound healing in both models, reversing impaired healing and promoting granulation tissue formation and enhanced neovascularization. The QSAZ@VPH hydrogel presents a promising strategy for diabetic ulcer therapy by targeting mitochondrial dysfunction and promoting tissue regeneration.