Carbon Dot‐Engineered Dual‐Action Exosomes Rescue Mitochondrial Homeostasis by Intercepting RIRR and Activating PGC‐1α in Severe Ischemia

Severe ischemic diseases are driven by oxidative stress and mitochondrial dysfunction. Macrophage‐derived extracellular vesicles (M2‐EVs) offer substantial regenerative potential, yet their clinical translation is hindered by microenvironmental degradation and a lack of targeting. We developed an engineered bio‐nano hybrid platform (M2‐EVs@CDs‐TPP) by integrating triphenylphosphonium (TPP)‐functionalized carbon dots (CDs) with M2‐EVs. This design enables a dual‐localization mode, wherein CDs‐TPP act as an antioxidant shield on the vesicle surface to enhance cellular uptake, while also serving as a subcellular navigator to precisely direct the therapeutic payload to damaged mitochondria. Mechanistically, the system exerts a dual‐action therapeutic effect. It chemically scavenges pathogenic mitochondrial ROS (mtROS) to disrupt the ROS‐induced ROS release (RIRR) cycle. Concurrently, this relief of oxidative stress synergizes with M2‐EVs to activate the Nrf2‐PGC‐1α metabolic regulatory hub. This biological reprogramming establishes robust biphasic antioxidant defenses (via HO‐1 and SOD2) and drives mitochondrial biogenesis (via NRF1/TFAM), reestablishing cellular ATP homeostasis. In vitro and in a murine critical limb ischemia model, this metabolic rewiring drove multidimensional tissue regeneration, encompassing angiogenesis, myoblast differentiation, and anti‐inflammatory macrophage polarization. This work provides a modular engineering strategy to overcome translational barriers of native EVs and highlights the clinical potential of targeting mitochondrial metabolism for pan‐ischemic disease therapy.