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 H₂O₂ scavenging and NAD⁺ regeneration. The nanozyme exhibits a Michaelis-Menten constant (K_m) of 4.64 mm for H₂O₂ decomposition, reflecting an 11.2-fold higher substrate affinity than natural catalase, and a K_m of 51.4 µm for NADH oxidation-significantly outperforming natural NADH oxidase. Density functional theory reveals that the FeCoN₆ active site enables synergistic Fe─Co interactions, lowering energy barriers for O₂ 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.