An Artificial Peroxynitrite-Resistant Superoxide Dismutase for Acute Kidney Injury Alleviation
- Small. 2025 Jun 26:e2503033. doi: 10.1002/smll.202503033.
- 1. Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Sciences and Engineering, School of Materials Science & Engineering, Hubei University, Wuhan, 430062, P. R. China.
- 2. College of Health Sciences and Engineering, Hubei University, Wuhan, 430062, P. R. China.
- 3. School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, P. R. China.
- 4. Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430015, P. R. China.
- 5. School of Life and Health Sciences, Hubei University of Technology, Wuhan, 430068, P. R. China.
- 6. Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China.
- 7. Department of Chemical Engineering, Columbia University, New York, 10027, USA.
- 8. Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, 430065, P. R. China.
- 9. Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, P. R. China.
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.