Atomically dispersed nanoactivators drive innate mitochondrial biogenesis for active neuroprotection in ischemic stroke

Mitigating mitochondrial bioenergetic failure is a pivotal yet formidable neuroprotective goal in treating cerebral ischemia-reperfusion injury (CIRI). However, conventional pharmacological interventions remain largely confined to passive antioxidant defense, which temporarily scavenges reactive oxygen species (ROS) without restoring organelle function. Here, we report a bimetallic nanoactivator (RMV) designed to drive active mitochondrial revival for rescuing ischemic tissues. RMV comprises atomically dispersed ruthenium sites anchored within an oxygen-deficient manganese hydroxide matrix via synergistic Ru–O–Mn bridges. Benefiting from its intrinsic mitochondriotropic properties, RMV effectively intercepts aberrant electron leakage and breaks the self-amplifying cycle of ROS-induced ROS release through cascade multi-enzyme mimetic activities. Importantly, transcriptomic profiling and ultrastructural analysis reveal that RMV transcends passive antioxidant defense by functioning as a bioactive switch. It revives the suppressed SIRT1–PGC1α–TFAM signaling axis, fundamentally driving mitochondrial biogenesis and the reconstruction of functionally intact respiratory chains. In a murine stroke model, RMV treatment induces a 1.52-fold expansion of the neuronal mitochondrial biomass under ischemic stress, thereby suppressing neuronal apoptosis, reducing infarct volumes, and favorably reshaping an M2-polarized neuroimmune microenvironment. These integrated effects yield robust and sustained neurofunctional recovery. Our study shifts the neuroprotective paradigm from reactive damage control to active mitochondrial biogenesis, offering an atomically engineered strategy for ischemic stroke management.