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

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-O₅/CN SAzyme) featuring square-pyramidal Mn-O₅ active sites and abundant hydroxyl groups is presented. Mn-O₅/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-O₅ coordination in Mn-O₅/CN SAzyme enhances its SOD-like activity and ONOO^- resistance. Mn-O₅/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-O₅/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-O₅ coordination structure in enhancing SOD-like activity and ONOO^- resistance, presenting a novel strategy for treating inflammatory diseases.