A Single‐Atom FeCo‐N ₆ Nanozyme with Dual Enzyme‐Mimicking Activity Reverses Redox Imbalance and Bioenergetic Collapse in Ischemic Stroke

Ischemic stroke (IS), a major cause of global disability, arises from mitochondrial dysfunction and reactive oxygen species (ROS) overproduction. Despite extensive research on ischemic stroke (IS), current therapies remain constrained by single‐target limitations, and a unified therapeutic strategy that concurrently mitigates reactive oxygen species (ROS) overload and restores mitochondrial function remains elusive. Herein, we report a single‐atom FeCo N/C nanozyme that uniquely integrates dual enzyme‐mimicking activities—catalase (CAT) and NADH oxidase—enabling simultaneous H 2 O 2 scavenging and NAD + regeneration. The nanozyme exhibits a Michaelis–Menten constant (K m ) of 4.64 m m for H 2 O 2 decomposition, reflecting an 11.2‐fold higher substrate affinity than natural catalase, and a K m of 51.4 µ m for NADH oxidation—significantly outperforming natural NADH oxidase. Density functional theory reveals that the FeCoN 6 active site enables synergistic Fe─Co interactions, lowering energy barriers for O 2 evolution. In HT22 neurons under oxygen‐glucose deprivation/reoxygenation, FeCo N/C reduces ROS, restores NAD + /NADH homeostasis, and boosts ATP synthesis, effectively suppressing apoptosis. In a murine middle cerebral artery occlusion/reperfusion model, a single intracerebroventricular dose (0.5 µL, 5 mg mL −1 ) reduces infarct volume from 58.0% to 32.9% and significantly improves neurological function. This work establishes a multitarget nanotherapeutic paradigm that bridges redox regulation and bioenergetic recovery, offering a clinically translatable strategy for ischemia‐reperfusion injury.