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This review provides a unified perspective on their design and therapeutic integration, organizing recent advances across multiscale material design, minimally invasive fabrication, spatiotemporal co\u2010engineering, and functional applications. Three emerging principles are identified: multiscale coupling bridges material architectures with cellular and tissue responses; spatiotemporal coordination integrates precise in vivo construction with dynamic material and biological evolution; and sensing\u2013regeneration feedback extends biohybrid systems from passive repair toward responsive therapeutic regulation. Building on these principles, we highlight machine learning\u2013assisted material discovery, multi\u2010site fabrication, and intelligent feedback control as key directions for developing adaptive, closed\u2010loop therapeutic systems. Together, these insights provide design guidance for translating minimally invasive multiscale biohybrid systems toward next\u2010generation patient\u2010centered healthcare.<\/jats:p>","DOI":"10.1002\/adma.75421","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:05:18Z","timestamp":1792580718000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Minimally Invasive In Vivo Fabrication of Multiscale Biohybrid Systems"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7459-2115","authenticated-orcid":false,"given":"Zhixing","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering National University of Singapore  Singapore 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