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Here, we reveal that the nanoscale spacing of adhesive ligands imposes stiffness\u2010dependent effects on mesenchymal stem cell (MSC) senescence. Wider spacing (distance 150\u00a0nm) accelerates aging on stiff hydrogels (50\u00a0kPa) but mitigates it on soft hydrogels (5\u00a0kPa), relative to dense spacing (distance 30\u00a0nm). Using a molecular clutch\u2010based theoretical model, we demonstrate that ligand spacing and matrix stiffness cooperatively regulate cell behaviors through focal adhesion assembly. Enhanced focal adhesion formation amplifies stress fiber\u2010generated traction forces and nuclear envelope tension, leading to increased chromatin accessibility and transcriptional activation of FOXO1, a central regulator of cellular senescence. These mechanistic insights are further validated in vivo. Collectively, these findings delineate a mechanotransduction mechanism through which nanoscale adhesive architecture and matrix stiffness cooperatively govern stem cell aging.<\/jats:p>","DOI":"10.1002\/adma.73896","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:36:41Z","timestamp":1785911801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nanoscale Adhesive Architecture Coordinates With Matrix Stiffness to Regulate Stem Cell Aging via Focal Adhesion\u2010Mediated Chromatin Remodeling and FOXO1 Activation"],"prefix":"10.1002","volume":"38","author":[{"given":"Jiacheng","family":"Lei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Department of Maxillofacial Plastic, Aesthetic and Trauma Surgery, West China Hospital of Stomatology Sichuan University Chengdu Sichuan P. R. China"},{"name":"College of Polymer Science and Engineering National Key Laboratory of Advanced Polymer Materials Sichuan University  Chengdu P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruihao","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Modern Mechanics University of Science and Technology of China  Hefei Anhui P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Department of Maxillofacial Plastic, Aesthetic and Trauma Surgery, West China Hospital of Stomatology Sichuan University Chengdu Sichuan P. R. 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