Intrinsically Mitochondria‐Targeting Nanozyme via Coordination‐Assembly of Natural Quercetin for Cascade Antioxidant Therapy of Cerebral Ischemia‐Reperfusion Injury

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 Fe 3+ . MCN currently generates Fe 2+ /Fe 3+ 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.