Apoptotic Vesicle Membrane-Mediated Targeted Endothelial Mitochondrial Transplantation-Clearance Therapy for Diabetic Wound Healing

Impaired mitophagy and the accumulation of damaged mitochondria are key drivers of endothelial cell (EC) dysfunction in diabetic wounds. While mitochondrial transplantation (MT) has demonstrated therapeutic potential in such mitochondrial damage-related diseases, its application is still thwarted by elusive mechanisms and practical hurdles such as poor targeting specificity and low delivery efficiency. Here, we reveal that MT acts by reactivating mitophagy to selectively eliminate dysfunctional mitochondria, thereby restoring mitochondrial homeostasis and rescuing EC functionality. To exploit this discovery, we engineer a biomimetic MT strategy through coating EC-derived apoptotic vesicle membrane (AVM) onto the surface of isolated mitochondria. The resulting mitochondria-AVM complex (Mito-AVM) leverages homologous targeting and phosphatidylserine-mediated "eat-me" signaling, achieving a remarkable 150% increase in delivery efficiency to ECs in diabetic wounds. Furthermore, we construct a 3-aminophenylboric acid-modified hyaluronic acid/polyvinyl alcohol hydrogel for the diabetic wound microenvironment, enabling reactive oxygen species/glucose-triggered sustained release of encapsulated Mito-AVM at the wound site. In summary, our work elucidates a fundamental mechanism of MT and provides an efficient and targeted strategy for MT therapy, offering fresh perspectives for diabetic wound treatment.