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.

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.

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.

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.

AKI 是一个具有高发病率和死亡率的重大公共卫生问题。不幸的是，AKI 尚无明确的治疗方法。RNA 干扰 (RNAi) 为基因治疗提供了一种新的有效方法来解决这个问题。

我们设计了具有靶向肽和治疗性 siRNA 的红细胞来源的细胞外囊泡 (REV)，以治疗小鼠模型中肾缺血/再灌注 (I/R) 损伤和单侧输尿管梗阻 (UUO) 后的实验性 AKI。噬菌体展示鉴定出与肾损伤分子 1 (Kim-1) 结合的肽。RNA 测序 (RNA-seq) 表征了缺血性肾脏的转录组，以探索潜在的治疗靶点。

I/R 损伤后，以 Kim-1 结合 LTH 肽 (REV _LTH ) 为靶标的 REV 有效地归巢并聚集在肾脏受损的小管处。我们确定了驱动炎症和纤维化的转录因子P65和Snai1作为潜在的治疗靶点。利用已建立的 REV _LTH，靶向P65和Snai1的 siRNA被有效地递送至缺血肾脏，从而阻断肾小管中 P-p65 和 Snai1 的表达。此外， P65和Snai1的双重抑制通过减轻肾小管间质炎症和纤维化，显着改善 I/R 和 UUO 引起的肾损伤，并有效地阻止向 CKD 的转变。

红细胞来源的细胞外囊泡平台以急性损伤的小鼠肾脏中的 Kim-1 为靶点，并为转录因子P65和Snai1递送 siRNA，从而减轻小管中的炎症和纤维化。