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

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 mol-ecules conferring renoprotection remain elusive. In this study, we characterized the protein composition of MSC-EVs using a proteomics approach and found that mitochondrial protein su-peroxide 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 integ-rity 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.