Metal‐Organic Complex‐Engineered Artificial Metalloenzymes With Synergistic Site and Cascade ROS Elimination to Treat Cerebral Ischemic‐Reperfusion Injury

ABSTRACT Ischemic stroke is a fatal cerebrovascular disease, and reperfusion, the primary approach for restoring blood supply, can lead to significant oxidative stress and subsequent damage to the cerebrovascular system. Developing strong antioxidant agents could be a solution, but it remains a Herculean challenge. Herein, inspired by the three‐dimensional coordination structures and active center of natural Mn‐superoxide dismutase, coupled with the synergistic monoatom/cluster sites found in antioxidases, we propose the de novo design of Mn‐organic complex‐supported Ru clusters (MnCP‐Ru) to function as an artificial metalloenzyme for cascade elimination of reactive oxygen species (ROS), aimed at protecting against cerebral ischemic‐reperfusion injury. Our studies show that Mn‐organic ligands increase the electron density of Ru clusters, thereby improving their binding to oxygen species and resulting in effective, cascade‐like antioxidase activities. Accordingly, the MnCP‐Ru can reduce the number of apoptotic neurons by attenuating ROS‐induced cell damage and exert powerful anti‐inflammatory effects by inhibiting lipid peroxidation, microglial and astrocyte activation in brain tissues, thus leading to powerful protection and repair of cerebral ischemia‐reperfusion injury. We believe the MnCP‐Ru biocatalyst, with its synergistic sites and cascade ROS elimination, offers effective antioxidative performance, paving the way for developing materials to treat ischemic‐reperfusion injury and other oxidative stress‐related diseases.