Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation and impaired immune tolerance, for which current therapies provide only partial and transient relief. Here, we introduce PrEXO-a23, a biomimetic nanotherapeutic engineered by fusing regulatory T cell (Treg)-derived exosomes with platelet membrane vesicles and conjugating interleukin-23 (IL-23) antibodies via a matrix metalloproteinase (MMP)-cleavable linker. This design exploits the inherent homing ability of platelets and Tregs, enabling PrEXO-a23 to preferentially accumulate in inflamed colonic tissues in murine IBD models. At the disease site, elevated MMP activity triggers antibody release to inhibit IL-23-mediated inflammation, while exosomal cargo reprograms dendritic cells and promotes Treg expansion, thereby restoring immune tolerance. This dual-action strategy significantly alleviates IBD, prevents complications like intestinal fibrosis and colitis-associated colorectal cancer, and shows p53-dependent efficacy in carcinogenesis prevention. These findings highlight PrEXO-a23 as a promising nanotherapeutic platform for durable immune reprogramming and long-term IBD management.
Data availability
The 16S rRNA gene sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive (SRA) under accession code PRJNA1400654. The RNA-seq data used in this study are available in the NCBI SRA database with accession number PRJNA1400962. All data underlying this study are available from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
This work was financially supported by the National Key Research and Development Program of China (No. 2023YFD1800105, L.M. and F.Z., No. 2022YFE0139800, L.M.), National Natural Science Foundation of China (82472163, F.Z., 32401260, M.O., 82272154, L.M., and 32371458, Y.L.), Tianjin Science Fund for Distinguished Young Scholars (22JCJQJC00120, L.M.), China Postdoctoral Science Foundation (2024M750242, M.O., 2025T180974, M.O.), Natural Science Foundation of Tianjin (23JCYBJC00470, F.Z.), the Fundamental Research Funds for the Central Universities, Peking Union Medical College (3332025196, M.O.), Postdoctoral Fellowship Program of CPSF (GZB20230085, M.O.), State Key Laboratory of Advanced Medical Materials and Devices Grant (24ZXZSSS00200, L.M.), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2024-I2M-TS-028 and 2025-I2M-XHJC-048, L.M.), and Guangdong Basic and Applied Basic Research Foundation (2025A1515010411 and 2024A1515220045, F.Z.).
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L.M., M.O., F.Z., and J.C. conceived and designed the project. J.C. and M.O. conducted all the experiments and analyzed the data. R.L., R.M., W.L., B.Z., L.Y., Y.F., X.W., W.Z., H.Z., and Z.M. provided technical input on this project. J.C. and M.O. wrote the original manuscript. L.M., M.O., Y.L., and F.Z. reviewed and revised the manuscript. J.Z. provided support for the manuscript revision. L.M., M.O., Y.L., and F.Z. supervised the overall research. All authors approved the manuscript.
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Cao, J., Luo, R., Miao, R. et al. Engineered exosome nanovesicles for delivery of antibodies to treat inflammatory bowel disease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69382-4
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DOI: https://doi.org/10.1038/s41467-026-69382-4
