Engineering Extracellular Vesicles to Target Kidney Fibrosis

Kidney fibrosis represents a maladaptive tissue repair response that ultimately becomes the final common pathway of most chronic kidney diseases. It emerges when repetitive or severe injury activates fibrogenic mechanisms that fail to resolve properly. As this activation persists, extracellular matrix components accumulate excessively and irreversibly, leading to progressive structural distortion and tissue scarring. Given the lack of effective antifibrotic therapies, strategies targeting the pathways driving this process are of considerable interest. Extracellular vesicles (EVs), small biological particles mediating intercellular communication, have emerged as promising tools for disease diagnosis and therapy. In this study, we engineered red blood cell–derived EVs (RBC-EVs) from healthy human donors with a Klotho peptide and investigated their effects on kidney fibrosis and proximal tubular function. Although naïve RBC-EVs are not expected to exert substantial antifibrotic effects, they were employed as a biocompatible delivery platform for therapeutic cargo. TGFβ-induced fibrosis in human proximal tubular epithelial cells resulted in increased expression of fibrotic markers, enhanced deposition of extracellular matrix components, and epithelial–mesenchymal transition, whereas treatment with engineered EVs partially prevented these outcomes by inhibiting activation of the TGFβ signaling pathway. Functionally, engineered EVs also counteracted mesenchymal features such as enhanced wound repair capacity and increased cell motility. To extend these findings, we employed a proximal tubule-on-a-chip model, demonstrating that engineered EV treatment similarly attenuated fibrotic marker induction and preserved epithelial organization preventing the loss of tubular integrity observed under TGFβ stimulation. In summary, RBC-EVs engineered with a Klotho peptide effectively target the TGFβ pathway, mitigate kidney fibrosis, and maintain proximal tubular structure, supporting their potential as a therapeutic strategy for chronic kidney disease