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Pancreatic stellate cells (PSCs) drive fibrosis by excessively secreting extracellular matrix proteins such as collagen I. Collagen I is thought to physically obstruct the delivery of macromolecules, such as albumin, antibodies, and nanomedicines. Apart from its structural role, collagen signals through dedicated cell surface receptors, such as the discoidin domain receptors (DDR) 1\/2. However, whether and how collagen signaling contributes to fibrotic barrier generation remains uncharacterized. Here, a 3D culture model of PDAC fibrosis constructed from patient PSCs is used to assess the contribution of DDR1\/2\u2010mediated collagen signaling. DDR1\/2 inhibition diminishes collagen I expression in PSCs to enhance macromolecular delivery. Moreover, MEK inhibitors exacerbate the fibrotic barrier by up\u2010regulating collagen I, an effect reversed by inhibiting DDR1\/2. Through isoform\u2010specific targeting, inhibiting DDR1, but not DDR2, is shown to be effective. Downstream of DDR, the involvement of the PI3K\/AKT\/mTOR pathway is demonstrated, particularly alternative mTOR complexes involving MEAK7 and GIT1. Altogether, the results show in vitro that DDR1\u2010mediated collagen signaling exacerbates the fibrotic barrier and may be targeted to enhance macromolecular drug delivery in PDAC.<\/jats:p>","DOI":"10.1002\/smll.202506926","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T09:35:23Z","timestamp":1761903323000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Collagen Signaling via DDR1 Exacerbates Barriers to Macromolecular Drug Delivery in a 3D Model of Pancreatic Cancer Fibrosis"],"prefix":"10.1002","volume":"21","author":[{"given":"Mayu","family":"Ohira","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biomedicine Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama University  1\u20101\u20101 Tsushima\u2010naka, Kita\u2010Ku Okayama\u2010Shi Okayama 700\u20108530 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Aramaki, Aoba\u2010Ku Sendai\u2010Shi Miyagi 980\u20108579 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Osada","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Theranostics Institute for Quantum Medical Science National Institutes for Quantum Sciences and Technology (QST)  4\u20109\u20101 Anagawa, Inage\u2010Ku Chiba\u2010Shi Chiba 263\u20108555 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Toyooka","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery and Breast and Endocrinological Surgery Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama University  2\u20105\u20101 Shikata\u2010cho, Kita\u2010Ku Okayama\u2010Shi Okayama 700\u20108558 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horacio","family":"Cabral","sequence":"additional","affiliation":[{"name":"Department of 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