Abstract
Sepsis-induced acute kidney injury (S-AKI) is a life-threatening condition driven by excessive immune inflammation, and effective treatments remain lacking. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to possess potent immunomodulatory activity. This study aimed to investigate the role and underlying mechanism of MSC-sEV in S-AKI. We established in vivo and in vitro models of S-AKI and employed techniques such as small RNA sequencing, transcriptome sequencing, luciferase reporter assays, and engineered gene editing to validate therapeutic efficacy and elucidate mechanisms. Results demonstrated that in S-AKI, MSC-sEV homed to injured kidneys and were internalized by renal tubular epithelial cells, significantly ameliorating renal damage and improving survival rates. Mechanistically, MSC-sEV delivered miR-125a-5p to target and inhibit TNFR2 expression, thereby blocking TNF-driven pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. Furthermore, engineered modification with the EXOMotif GGAG significantly enhanced MSC-sEV delivery of miR-125a-5p and inhibition of TNFR2. In conclusion, this study demonstrates that MSC-sEV represent a promising drug delivery vehicle with substantial targeted therapeutic potential for S-AKI.
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Funding
This study was supported by grants from the National Natural Science Foundation of China (No.82230022, 82030024, and 81720108007), the National Key Research and Development Program of China (2022YFC2502500) to Bi-Cheng Liu. This study was supported by additional grants from the National Natural Science Foundation of China (82200772), the Natural Science Foundation of Jiangsu Province grant (BK20220828), and the Fundamental Research Funds for the Central Universities (2242023R40030) to Tao-Tao Tang, and the National Natural Science Foundation of China (82241045, 82122011) to Lin-Li Lv. This work was also supported by Shenzhen Science and Technology Innovation Program (KJZD20230923115201003).
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All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Animal Care Committee of Southeast University. [Approval title: Therapeutic effect of extracellular vesicles derived from human umbilical cord mesenchymal stem cells on renal injury in mice. Approval No.: 20220224039. Date: February 24, 2022]. The work has been reported in line with the ARRIVE guidelines 2.0. The donor of hucMSCs has provided informed consent, and all procedures were approved by Clinical Research Ethics Committee of Zhongda Hospital Affiliated to Southeast University (Approval title: Mechanism study of extracellular vesicles derived from umbilical cord mesenchymal stem cells remodeling inflammatory microenvironment in renal tubule interstitial. Approval No.: 2023ZDSYLL118-P01. Date: May 11, 2023). The work described has been carried out in accordance with Declaration of Helsinki for experiments involving humans.
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Chen, F., Tang, TT., Chen, ZQ. et al. Mesenchymal stem cell-derived small extracellular vesicles suppress pyroptosis by delivering miR-125a-5p to improve acute kidney injury in sepsis. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03143-6
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DOI: https://doi.org/10.1038/s41420-026-03143-6
