The kidneys are susceptible to hypoxia, proteinuria, and toxins, which can trigger acute kidney injury (AKI). Maladaptive repair of AKI results in the development of chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) represents a pivotal mechanism underlying renal interstitial fibrosis (RIF). Myofibroblasts represent the primary effector cells of RIF with over 30% derived from renal tubular epithelial cells (RTECs). RTECs play a crucial role in CKD by generating part of EMT, while Snail1 is an effective inducer of EMT. Therefore, silencing Snail1 in RTECs and blocking the EMT process represents an original approach for treating RIF. Here, the positively charged l-arginine (L-Arg) and the hydrophobic fragment stearic acid (SA) were introduced on the chitosan oligosaccharide to afford a dual-targeted COA-SA micelle via size-, charge- and active targeting effects. The micelle overcomes the substantial disparity in physical and chemical properties between hydrophilic nucleic acid macromolecules and the anti-inflammatory small molecule celastrol and successfully establishes a codelivery platform. In vivo, COA-SA micelles can traverse the blood circulation, and glomerular filter, and overcome intracellular barriers to achieve efficient and precise drug delivery to RTECs. This results in the successful reversal of the EMT process in RTECs, thereby achieving a favorable anti-fibrosis effect.

Renal tubular epithelial cells  /  Epithelial-mesenchymal transition  /  Glomerular filtration barrier  /  Snail siRNA  /  Active and passive dual targeting  /  EMT inactivation  /  Acute kidney injury  /  Renal fibrosis