Engineered extracellular vesicles promote the repair of acute kidney injury by modulating regulatory T cells and the immune microenvironment

Abstract Background Acute kidney injury (AKI) is a common and severe clinical condition. However, the underlying mechanisms of AKI have not been fully elucidated, and effective treatment options remain limited. Studies have shown that immune cells play a critical role in AKI, with regulatory T cells (Tregs) being one of the most important immunosuppressive lymphocytes. Tregs proliferation can attenuate AKI, whereas depletion exacerbates kidney injury. Given that endothelial cells (ECs) are the initial cells that interact with immune cells when they invade the tissue parenchyma, ECs are closely associated with immune reactions. Methods and Results In this study, P-selectin binding peptide-extracellular vesicles (PBP-EVs) that target and repair ECs are engineered. Transcriptome sequencing reveals that PBP-EVs reduce the expression of inflammatory genes in AKI mice. Using high-resolution intravital two-photon microscopy (TPM), an increased recruitment of Tregs in the kidneys of AKI Foxp3-EGFP transgenic mice following PBP-EVs treatment is observed, as well as significant Lgr5+ renal stem cell proliferation in AKI Lgr5-CreERT2; R26mTmG mice. Additionally, PBP-EVs treatment result in reduced infiltration of inflammatory cells, pathological damage and fibrosis of AKI mice. Upon depletion of Tregs in Foxp3-DTR transgenic mice, we observe diminished therapeutic effect of PBP-EVs on AKI. Conclusions The experimental results indicate that PBP-EVs can promote the repair and regeneration of AKI by mitigating endothelial cell damage and subsequently modulating Tregs and the immune microenvironment. These findings provide novel insights and strategies for the treatment of AKI.