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To address this, we have designed nanofibrous composite hydrogels by co\u2010assembling peptide amphiphiles (PAs) with tumor\u2010specific ECM macromolecules, including collagen type I, hyaluronan, laminin alpha 4, and fibronectin, enabling control over composition and nanofibre organization, including either randomly oriented (rPA) or aligned (aPA) nanofibers. These hydrogels recapitulate key biochemical composition, fibrillar architecture, and mechanical properties of the colorectal cancer TME (CRC\u2010TME). Using colorectal cancer cell lines and patient\u2010derived organoids (PDOs), we demonstrate that rPA\u2010based hydrogels support long\u2010term organoid growth (21 days), preserving tumor\u2010specific morphology (compact, cystic structures) and transcriptional profiles characteristic of cell\u2010ECM interactions compared to aPA hydrogels. Transcriptomic analysis revealed rPA\u2010ECM hydrogels upregulate ECM remodeling genes while maintaining lineage\u2010specific differentiation, enabling precise interrogation of matrix\u2010driven signaling. By integrating tumor\u2010specific ECM macromolecules with architecturally defined nanofibers, this platform bridges the gap between simplistic in vitro models and clinical tumor complexity. This approach offers a complex, yet defined and reproducible, platform with significant potential to recapitulate TMEs for personalized medicine.<\/jats:p>","DOI":"10.1002\/adhm.202505943","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T05:04:35Z","timestamp":1780117475000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co\u2010Assembling 3D In Vitro Model to Recreate the Colorectal Tumor Microenvironment"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9717-6661","authenticated-orcid":false,"given":"Magda","family":"Mart\u00ednez\u2010Espuga","sequence":"first","affiliation":[{"name":"Department of Chemical and Environmental Engineering University of Nottingham  Nottingham UK"},{"name":"Biodiscovery Institute University of Nottingham  Nottingham 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