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Background  AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue.    Methods  We engineered red blood cell–derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets.    Results  REVs targeted with Kim-1–binding LTH peptide (REV LTH ) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors  P65  and  Snai1  that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REV LTH , siRNAs targeting  P65  and  Snai1  were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of  P65  and  Snai1  significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD.    Conclusions  A red blood cell–derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors  P65  and  Snai1 , alleviating inflammation and fibrosis in the tubules.

Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI