Abstract

The therapeutic failure in diabetic wounds often stems from a pathological disconnect between antioxidant signaling and mitochondrial repair, a core limitation that conventional antioxidative approaches fail to address. Although targeting mitochondrial dysfunction presents a promising therapeutic avenue, conventional strategies often fail to reconcile efficient targeting of impaired organelles with high biocompatibility. To address this limitation, a biohybrid nanovesicle (designated DHM@mtABV) was engineered by fusing ADSC-derived nanovesicles (ANVs) with synthetic liposomes that co-encapsulate the antioxidant dihydromyricetin (DHM) and the mitochondria-targeting ligand TPP (DHM@mtLipo). The resulting DHM@mtABV nanovesicles demonstrated exceptional biocompatibility and pronounced mitochondrial accumulation. Functionally, DHM@mtABV effectively broke the vicious cycle of oxidative stress by simultaneously scavenging mitochondrial ROS and activating the cytoprotective NRF2 signaling pathway. Consequently, DHM@mtABV treatment significantly restored mitochondrial membrane potential and calcium homeostasis, enhanced cellular proliferation and migration under oxidative stress, and markedly accelerated wound closure in a diabetic mouse model. This work not only presents a potent therapeutic but also validates a generalizable biohybrid strategy that reconstitutes the critical link between subcellular targeting and systemic tissue repair, offering a transformative paradigm for treating refractory diabetic wounds.