Abstract

Mitochondrial dysfunction, culminating in oxidative stress-driven release of mitochondrial DNA (mtDNA) and subsequent inflammatory activation, constitutes a central pathogenic axis in cerebral ischemia-reperfusion injury. Disrupting this axis requires precise antioxidant delivery to neuronal mitochondria, a major therapeutic hurdle. Here, we uncover that the natural flavonoid quercetin (Quer) possesses an intrinsic ability to bind mitochondrial outer membrane proteins, revealing its unexploited potential as a natural mitochondrial-targeting ligand. Leveraging this discovery, we engineered an ultrasmall mitochondria-targeting cascade nanozyme through coordination-driven self-assembly of the natural flavonoid Quer with Fe3+. MCN currently generates Fe2+/Fe3+ dual-valence centers that confer potent, superoxide dismutase-catalase cascade catalytic enzyme activities. We further confirmed that the MCN traverse the compromised blood-brain barrier, localize within the ischemic brain, and are selectively delivered to neuronal mitochondria in a rodent stroke model. Through its cascade elimination of key ROS, MCN stabilizes mitochondrial function and prevents mtDNA leakage. By blocking the released mtDNA from activating the cGAS-STING pathway in microglia, MCN reprograms the neuroinflammatory microenvironment and robustly attenuates brain injury, leading to significant functional recovery. This work establishes a paradigm of transforming inherent bioactivity of natural products into targeted catalytic nanomedicines, offering a precise therapeutic strategy for mitochondrial-centric diseases.