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While chemical modifications are routinely used to tune hydrogel properties, it remains unclear whether these modifications mediate cell fate. Previous work has shown that cells deposit newly synthesized (nascent) ECM at the cell\u2010hydrogel interface. Here, we demonstrate that this nascent ECM interface regulates how cells interpret chemical modifications. Using hydrogels with varied chemical modifications, we isolated the effects of chemical modification on nascent ECM and cell fate. Nascent ECM deposition increased as a function of hydrogel modification and with distinct matrisome compositions. While low\u2010modification hydrogels promoted cell differentiation, high modifications increased cell proliferation. Perturbing cell\u2010 nascent ECM interactions reversed this cell fate. Our findings reveal that nascent ECM regulates cell fate by converting hydrogel cues into signals that control cell fate. This tri\u2010directional interplay among hydrogel chemical modifications, nascent ECM, and cell fate reframes how we interpret cell\u2010hydrogel interactions.<\/jats:p>","DOI":"10.1002\/advs.77895","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nascent Extracellular Matrix Converts Biomaterial Cues into Cell Fate Decisions"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4874-7149","authenticated-orcid":false,"given":"Joshua Y.","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia USA"},{"name":"Center for Precision Engineering for Health (CPE4H) University of Pennsylvania  Philadelphia 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