Charge-reversed small extracellular vesicles from human adipose-derived mesenchymal stromal cells attenuate renal fibrosis postacute kidney injury by inhibiting epithelial-mesenchymal transition progression in SD rat model

Abstract

Approximately 25% of patients with acute kidney injury (AKI) progress to chronic kidney disease, driven by the transition of renal tubular epithelial cells from epithelial to mesenchymal cells. Recent studies show that adipose-derived mesenchymal stromal cell-derived small extracellular vesicles (AMEV) can ameliorate renal fibrosis and injury. However, owing to poor retention, the limited bioavailability of AMEV hamper their therapeutic application. In this study, AMEV were extracted and modified with an ε-polylysine-polyethylene-distearoylphosphatidylethanolamine (PPD) polymer, which facilitated the reversal of the AMEV surface charge, thereby generating positively charged AMEV for the treatment of AKI. In a rat model of AKI, PPD modification significantly enhanced the renal retention of AMEV and effectively alleviated renal pathological damage. Further, RNA sequencing revealed that AMEV derived from adipose-derived mesenchymal stromal cells contains abundant microRNAs. We found that PPD modification significantly enhanced the bioavailability of AMEV and improved therapeutic effects in both in vivo and in vitro experiments. Furthermore, miR-100 enriched in AMEV targeted mTOR and suppressed the epithelial-mesenchymal transition phenotype of renal tubular epithelial cells, thereby alleviating renal fibrosis and promoting recovery of renal function postischemia-reperfusion. Overall, this study presents a promising therapeutic strategy and identifies clinical targets to combat renal fibrosis.