Nanotherapeutic Strategy via ADSC-mitoEVs Rescues Ischemic Angiogenesis through Mitophagy and Mitochondrial Metabolic Reprogramming

Ischemic vascular diseases are critically associated with mitochondrial dysfunction in endothelial cells, leading to impaired angiogenesis and compromised tissue repair. Although mitochondrial transfer has emerged as a promising therapeutic strategy for revascularization, its clinical translation has been hindered by inefficient delivery systems. In this study, we show that mitochondrial-enriched extracellular vesicles derived from adipose-derived stem cells (ADSC-mitoEVs) function as an efficient nanotherapeutic, restoring angiogenic function both in vitro and in a murine model of diabetic hindlimb ischemia. Mechanistically, the uptake of ADSC-mitoEVs triggered PINK1/Parkin-mediated mitophagy in recipient endothelial cells, a process essential for initiating angiogenesis. Moreover, ADSC-mitoEVs directly delivered functional mitochondrial proteins, including superoxide dismutase 2 (SOD2), into the endogenous mitochondrial network, which enhanced antioxidant defense and improved bioenergetic capacity independently of mitophagy, as shown by reduced reactive oxygen species and elevated ATP production even in PINK1-silenced cells. Our results demonstrate ADSC-mitoEVs as a versatile, cell-free nanotherapeutic that promotes mitochondrial quality control and metabolic reprogramming, offering a potent therapeutic avenue for ischemic vascular diseases.