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Here, we identify focal adhesion kinase (FAK\/\n                    <jats:italic>PTK2<\/jats:italic>\n                    ) as a central mechanobiological regulator that couples ECM remodeling with cellular mechanics to control NP transport and cellular uptake. The ECM derived from patients' tumors exhibited increased stiffness and collagen density, which severely restricted NP penetration, while\n                    <jats:italic>PTK2<\/jats:italic>\n                    emerged as a key integrin\u2010associated signaling hub linked to ECM organization. FAK depletion or inhibition disrupted ECM homeostasis, significantly enhanced NP penetration and cellular uptake. Mechanistically, FAK loss reduced cellular stiffness and cytoskeletal tension while increasing membrane deformability and transcriptionally reprogramming endocytic pathways, with clathrin\u2010mediated endocytosis as the dominant route. In vivo, FAK ablation remodeled the tumor stroma to enhance NP accumulation and penetration, and the combination of FAK inhibition with chemotherapy demonstrated potent antitumor efficacy. Together, these results establish a multiscale mechanistic paradigm in which FAK integrates ECM biophysics, cellular mechanics, and endocytic regulation to gatekeep nanomedicine delivery. Targeting FAK offers a potential strategy to enhance therapeutic penetration and efficacy in solid tumors.\n                  <\/jats:p>","DOI":"10.1002\/advs.78146","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:00:18Z","timestamp":1792033218000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FAK Mediated Coordination of Extracellular Matrix Remodeling and Cellular Mechanics Impairs Nanomedicine Delivery in Solid Tumors"],"prefix":"10.1002","author":[{"given":"Tian","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1579-2138","authenticated-orcid":false,"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4857-2908","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"},{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1595-9700","authenticated-orcid":false,"given":"Xiang","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4510-8261","authenticated-orcid":false,"given":"Junjie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; Institute Sichuan Cancer Center and School of Life Science and Technology University of Electronic Science and Technology of China Chengdu Sichuan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &amp; 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