ABSTRACT: Background: Cisplatin is a widely used chemotherapeutic agent for various solid tumors. However, its use is often limited by nephrotoxicity, which can lead to acute kidney injury and, with repeated exposure, cumulative tubular damage and chronic renal dysfunction. Induced mesenchymal stem cell-derived extracellular vesicles (iMSC-EVs) have emerged as a promising cell-free therapeutic approach because of their anti-inflammatory, anti-apoptotic, and regenerative properties. The therapeutic efficacy of iMSC-EVs in cumulative cisplatin nephrotoxicity remains unclear. Methods: Male C57BL/6 mice were subjected to renal injury by intraperitoneal cisplatin administration at 9 mg/kg once weekly for five cycles. After the final cisplatin injection, mice received intravenous PBS or iMSC-EVs at doses of 200 or 400 μg every 3 days for five doses. Renal injury, fibrosis, inflammation, cell-death signaling, oxidative stress, and peritubular capillary loss were evaluated by histology, immunoblotting, immunostaining, and quantitative polymerase chain reaction. RNA sequencing of renal tissue was performed to identify pathways regulated by iMSC-EV treatment. Results: iMSC-EVs ameliorated repeated cisplatin-induced renal injury in a dose-associated manner, with the 400 μg group showing more pronounced therapeutic effects. iMSC-EV treatment reduced collagen deposition, tubular damage, immune-cell infiltration, and peritubular capillary loss. Fibrosis-related markers and inflammatory mediators were suppressed by iMSC-EV. RNA-sequencing of renal tissues revealed that iMSC-EV treatment modulated and partially reversed RLDC-induced transcriptional alterations, particularly those associated with inflammatory, immune, and extracellular matrix-related pathways. Conclusion: iMSC-EVs mitigated key pathological features of repeated cisplatin-induced kidney injury, with the most consistent effects observed at the 400 μg dose. These findings support iMSC-EVs as a promising cell-free therapeutic strategy for tubulointerstitial fibrosis induced by cumulative cisplatin nephrotoxicity.
