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 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.