2. Academic Validation
  3. An Artificial Peroxynitrite-Resistant Superoxide Dismutase for Acute Kidney Injury Alleviation

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

  • Small. 2025 Jun 26:e2503033. doi: 10.1002/smll.202503033.
Fengxian Zhang 1 2,  Ping Gao 3 4,  Min Qi 1 2,  Junjie Hu 3,  Xiuxun Wu 3,  Cao Li 5,  Zechao Zhuang 6 7,  Zhenpeng Qiu 3 8 9,  Ziqiang Xu 1 2
Affiliations

Affiliations

  • 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.
PMID: 40574376 DOI: 10.1002/smll.202503033
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-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.

Keywords

NLRP3 inflammasomes; acute kidney injury; peroxynitrite‐resistant; single‐atom nanozyme; superoxide dismutase.

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