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<p>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. </p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Yuan-zheng Zhu,
  • Min-chen Zhang,
  • Xue-er Li,
  • Xing-hong Zeng,
  • Xue-ting Gong,
  • Yu-zi Wu,
  • Ze-jun Dong,
  • Shu Wu,
  • Xue-fei Liu,
  • Abdul Haseeb Khan,
  • Yang-yan Yi

摘要

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.

Graphical abstract