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However, conventional tissue culture plate (TCP)\u2010based 2D adherent cultures or widely used ultra\u2010low attachment (ULA) spheroid systems often compromise differentiation potential and therapeutic efficacy of hADSCs. Here, we report a synthetic polymer matrix, poly\u2010Z, that enables the formation of hADSC spheroids with significantly enhanced biological functions. Compared to ULA or TCP culture systems, poly\u2010Z\u2010cultured hADSC spheroids exhibited improved cell viability, enriched extracellular matrix deposition, elevated pluripotency marker expression, and superior tri\u2010lineage differentiation capacity. Notably, poly\u2010Z spheroids displayed a distinct immunomodulatory signature characterized by significantly elevated secretion of indoleamine\u2010pyrrole 2,3\u2010dioxygenase (IDO) and prostaglandin E2 (PGE2), and showed enhanced in vivo persistence after transplantation. In mouse models of acute colitis and acetaminophen\u2010induced liver injury, poly\u2010Z\u2010cultured hADSC spheroids markedly alleviated inflammation, reduced tissue damage, and modulated pro\u2010 and anti\u2010inflammatory cytokine levels more effectively than ULA or TCP\u2010derived cells. These findings establish the poly\u2010Z matrix as a potent 3D culture platform that enhances the functional and therapeutic potential of hADSCs for clinical applications.<\/jats:p>","DOI":"10.1002\/advs.202518704","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T19:30:06Z","timestamp":1774985406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polymer Matrix\u2010Based 3D Culture Significantly Enhances the Differentiation and Immunomodulatory Functions of Human Adipose\u2010Derived Stem Cells"],"prefix":"10.1002","volume":"13","author":[{"given":"Changjin","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for the BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center For Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology 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Tasnim","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for the BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center For Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-586X","authenticated-orcid":false,"given":"Sangyong","family":"Jon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for the BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center For Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of 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