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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\u2010targeting ligand. Leveraging this discovery, we engineered an ultrasmall mitochondria\u2010targeting cascade nanozyme through coordination\u2010driven self\u2010assembly of the natural flavonoid Quer with Fe\n                    <jats:sup>3+<\/jats:sup>\n                    . MCN currently generates Fe\n                    <jats:sup>2+<\/jats:sup>\n                    \/Fe\n                    <jats:sup>3+<\/jats:sup>\n                    dual\u2010valence centers that confer potent, superoxide dismutase\u2010catalase cascade catalytic enzyme activities. We further confirmed that the MCN traverse the compromised blood\u2013brain 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\u2010STING 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\u2010centric diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.76038","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T08:31:59Z","timestamp":1781166719000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Intrinsically Mitochondria\u2010Targeting Nanozyme via Coordination\u2010Assembly of Natural Quercetin for Cascade Antioxidant Therapy of Cerebral Ischemia\u2010Reperfusion Injury"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenxuan","family":"Zheng","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Hunan University of Chinese Medicine  Changsha China"},{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha 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