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Recent advancements in identifying reprogramming factors and understanding molecular barriers have enabled efficient generation of therapeutically relevant cells. Yet, the clinical application of in vitro\u2010derived reprogrammed cells is hampered by the immature phenotype, hostile microenvironments, low engraftment, and poor survival after transplantation. In vivo direct reprogramming of tissue\u2010resident cells within their native tissue microenvironment offers a compelling alternative to overcome these barriers. Harnessing biochemical and biophysical cues of the tissue microenvironment, this approach facilitates the acquisition of molecular and functional features resembling endogenous cells. This review summarizes the current understanding of in vivo direct reprogramming, covering mechanisms, key reprogramming factors, and delivery strategies, and explores therapeutic applications across organ systems. Finally, key challenges such as delivery efficiency, incomplete understanding of tissue cues, and limited mechanistic insights, along with emerging strategies, are discussed.<\/jats:p>","DOI":"10.1002\/advs.77370","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:52:24Z","timestamp":1789980744000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vivo Direct Reprogramming: Current Progress and Future Prospects from Mechanisms to Therapeutic Application"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-5043","authenticated-orcid":false,"given":"Rishabh Deo","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University (SKKU) School of Medicine  Suwon Republic of 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