Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI
Tao‐Tao Tang, Bin Wang, Zuo‐Lin Li, Yi Wen, Songtao Feng, Min Wu, Dan Liu, Jing-Yuan Cao, Qing Yin, Di Yin, Yuqi Fu, Yue-Ming Gao, Zhaoying Ding, Jingyi Qian, Qiuli Wu, Lin‐Li Lv, Bi‐Cheng Liu
Abstract
Significance Statement AKI is a frequent clinical problem without definitive therapies. We developed an efficient RNAi therapy against AKI by engineering red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs. REVs targeted with Kim-1–binding peptide LTH efficiently delivered P65 and Snai1 siRNAs to the injured tubules, leading to reduced expression of P-p65 and Snai1. Dual suppression of P65 and Snai1 inhibited renal inflammation and fibrosis in mice subjected to ischemia/reperfusion injury and unilateral ureteral obstruction, and blunted the chronic progression of ischemic AKI. This study provides an efficient platform, REV LTH, for the targeted delivery of therapeutics into injured tubular cells, and suggests the viability of targeting P65 and Snai1 as a therapeutic avenue for AKI. 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.