Nanotherapeutic strategy via ADSC-mitoEVs rescues ischaemic angiogenesis through mitophagy and mitochondrial metabolic reprogramming

Ischaemic vascular diseases are critically linked to mitochondrial dysfunction in endothelial cells, which impairs angiogenesis and tissue repair. Although mitochondrial transplantation has emerged as a promising regenerative strategy, its clinical translation remains limited by inefficient delivery and poor retention in target tissues. Here, we demonstrate that mitochondrial-enriched extracellular vesicles derived from adipose-derived stem cells (ADSC-mitoEVs) function as an efficient cell-free nanotherapeutic that restores angiogenic function both in vitro and in a murine model of diabetic hindlimb ischaemia. Mechanistically, ADSC-mitoEV uptake triggers PINK1/Parkin-mediated mitophagy in recipient endothelial cells, a process essential for initiating angiogenesis. Moreover, ADSC-mitoEVs also directly deliver functional mitochondrial proteins, including superoxide dismutase 2 (SOD2), into the endogenous mitochondrial network, which enhances antioxidant activity and improves bioenergetic capacity independently of mitophagy, as demonstrated by reduced reactive oxygen species and elevated ATP production even in PINK1-silenced cells. Our findings establish ADSC-mitoEVs as a versatile cell-free nanotherapeutic that promotes mitochondrial quality control and metabolic reprogramming, offering a potent therapeutic avenue for ischaemic vascular diseases.