Alleviation of ischemia-reperfusion induced renal injury by chemically modified SOD2 mRNA delivered via lipid nanoparticles

Yutong Hou; Sihao Lin; Jia Xia; Yu Zhang; Yanan Yin; Masha Huang; Yingjie Xu; Wen Yang; Yingjian Zhu

doi:10.1016/j.omtn.2023.102067

Alleviation of ischemia-reperfusion induced renal injury by chemically modified SOD2 mRNA delivered via lipid nanoparticles

Mol Ther Nucleic Acids. 2023 Oct 26:34:102067. doi: 10.1016/j.omtn.2023.102067. eCollection 2023 Dec 12.

Authors

Yutong Hou¹, Sihao Lin², Jia Xia³, Yu Zhang¹, Yanan Yin¹, Masha Huang¹, Yingjie Xu^{1

4

5

6}, Wen Yang^{1

7}, Yingjian Zhu²

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
² Department of Urology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, P.R. China.
³ Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China.
⁴ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
⁵ RNAcure Biopharma, Shanghai, P.R. China.
⁶ Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai, P.R. China.
⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai, P.R. China.

Abstract

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury, which is a serious clinical condition with no effective pharmacological treatment. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) significantly alleviate kidney IRI; however, the underlying mechanisms and key molecules conferring renoprotection remain elusive. In this study, we characterized the protein composition of MSC-EVs using a proteomics approach and found that mitochondrial protein superoxide dismutase 2 (SOD2) was enriched in MSC-EVs. Using lipid nanoparticles (LNP), we successfully delivered chemically modified SOD2 mRNA into kidney cells and mice with kidney IRI. We demonstrated that SOD2 mRNA-LNP treatment decreased cellular reactive oxygen species (ROS) in cultured cells and ameliorated renal damage in IRI mice, as indicated by reduced levels of serum creatinine and restored tissue integrity compared with the control mRNA-LNP-injected group. Thus, the modulation of mitochondrial ROS levels through SOD2 upregulation by SOD2 mRNA-LNP delivery could be a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

Keywords: MT: Delivery Strategies; SOD2; chemically modified mRNA; extracellular vesicles; kidney ischemia-reperfusion injury; mesenchymal stem cell; mitochondria.