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Exercise can affect skeletal muscle EV secretion and that this process regulates the systemic health\u2010promoting role of exercise, suggesting that fine\u2010tuning of endogenous tissue EV secretion may provide a new therapeutic avenue. Here, this work reports that in vivo reprogramming of EV secretion via metabolic engineering is a promising strategy for treating chronic diseases. Briefly, exercise enhanced mitochondrial metabolism and EV production in healthy skeletal muscles, and EVs from healthy skeletal muscles subjected to exercise or metabolic engineering (boosting mitochondrial biogenesis via AAV\u2010mediated muscle\u2010specific TFAM overexpression) exerted cellular protective effects in vitro. In injured skeletal muscles, in vivo metabolic engineering therapy could reprogram EV secretion patterns (reducing pathological EV compositions while increasing beneficial EV compositions) by regulating multiple EV biogenesis and cargo sorting pathways. Reprogrammed muscle\u2010derived EVs could reach major organs and tissues via the circulation and then simultaneously attenuated multiple\u2010tissue (e.g., muscle and kidney) injury in chronic kidney disease. This study highlights that in vivo reprogramming of tissue\u2010derived EVs via a metabolic engineering approach is a potential strategy for treating diverse chronic diseases.<\/jats:p>","DOI":"10.1002\/advs.202415556","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T05:57:49Z","timestamp":1743487069000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Vivo Reprogramming of Tissue\u2010Derived Extracellular Vesicles for Treating Chronic Tissue Injury Through Metabolic Engineering"],"prefix":"10.1002","volume":"12","author":[{"given":"Meng","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology Frontiers Science Center for Disease\u2010related Molecular Network West China Hospital Sichuan University  Chengdu 610041 China"},{"name":"Department of Emergency Guizhou Provincial 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