An Artificial Peroxynitrite‐Resistant Superoxide Dismutase for Acute Kidney Injury Alleviation

Abstract Manganese superoxide dismutase (Mn‐SOD) is the most common natural antioxidant enzyme that defends cells against oxidative stress. However, it is intrinsically vulnerable to nitration by peroxynitrite (ONOO − ) to result in accumulation of reactive oxygen species and inducement of acute kidney injury (AKI). Designing Mn‐SOD mimics that are both active and resistant to ONOO − is essential for advancing artificial enzymes and broadening the application of enzymatic catalytic therapies. Herein, an artificial manganese‐based single‐atom nanozymes (Mn‐O 5 /CN SAzyme) featuring square‐pyramidal Mn‐O 5 active sites and abundant hydroxyl groups is presented. Mn‐O 5 /CN SAzyme demonstrates excellent biocompatibility, superior SOD‐like activity, and tolerance to ONOO − , positioning it as a promising artificial enzyme mimics for alleviating AKI. Theoretical calculations suggest that the square‐pyramidal Mn‐O 5 coordination in Mn‐O 5 /CN SAzyme enhances its SOD‐like activity and ONOO − resistance. Mn‐O 5 /CN SAzyme has high antioxidant efficacy toward HK‐2 cells. It significantly reduces renal oxidative stress and inflammation in AKI mice, without any side effects. Mechanistically, Mn‐O 5 /CN SAzyme alleviates AKI by suppressing the pro‐inflammatory cytokine cascade driven by the NOD‐like receptor protein 3 (NLRP3)/caspase‐1/gasdermin D pathway. This study highlights the crucial role of the Mn‐O 5 coordination structure in enhancing SOD‐like activity and ONOO − resistance, presenting a novel strategy for treating inflammatory diseases.