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Excessive collagen deposition, hyaluronic acid accumulation, elevated interstitial fluid pressure, and remodeling by cancer-associated fibroblasts generate a dense stromal architecture that limits uniform intratumoral penetration of nanoscale therapeutics. Consequently, many nanocarrier systems, despite optimized pharmacokinetic properties, fail to achieve effective drug delivery beyond perivascular tumor regions. Recent advances in materials engineering have enabled the development of ECM-responsive nanomedicine platforms that integrate ECM-targeting ligands, protease-responsive activation mechanisms, stromal remodeling strategies, and physically adaptive carrier architectures to overcome tumor stromal barriers. These approaches transform the ECM from a transport barrier into a programmable therapeutic interface, enabling selective activation, enhanced stromal penetration, and spatially controlled drug release. In parallel, enzyme-mediated stromal remodeling and cancer-associated fibroblast reprogramming have emerged as complementary strategies for restoring interstitial transport and improving intratumoral drug distribution. This review summarizes recent progress in engineering ECM-responsive nanomedicine to overcome tumor stromal barriers, with emphasis on ECM-targeted delivery, protease-responsive nanomedicine, enzyme-mediated matrix remodeling, physically adaptive nanocarriers, and ECM-guided immunomodulatory strategies. Emerging spatial omics technologies and ECM-mimetic modeling platforms are also discussed as enabling tools for the rational design of next-generation delivery systems. Collectively, these advances support a transition from passive accumulation-based delivery toward programmable stromal interface engineering for more effective cancer nanomedicine.<\/jats:p>","DOI":"10.1021\/acsabm.6c01118","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:02:00Z","timestamp":1786388520000},"page":"7808-7831","source":"Crossref","is-referenced-by-count":1,"title":["Engineering ECM-Responsive Nanomedicine to Overcome Tumor Stromal Barriers"],"prefix":"10.1021","volume":"9","author":[{"given":"Kalpana","family":"Swain","sequence":"first","affiliation":[{"name":"Calcutta Institute of Pharmaceutical Technology and AHS , ,","place":["Howrah, India, 711316"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3113-6926","authenticated-orcid":true,"given":"Satyanarayan","family":"Pattnaik","sequence":"additional","affiliation":[{"name":"Calcutta Institute of Pharmaceutical Technology and AHS , ,","place":["Howrah, India, 711316"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"issue":"1","key":"2026092215072880900_cit1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41392-023-01536-y","article-title":"Nanomedicine in Cancer Therapy","volume":"8","author":"Fan","year":"2023","journal-title":"Signal Transduction Targeted Ther."},{"issue":"12","key":"2026092215072880900_cit2","first-page":"3039","article-title":"Transport of Molecules in the Tumor Interstitium: A Review","volume":"47","author":"Jain","year":"1987","journal-title":"Cancer Res."},{"key":"2026092215072880900_cit3","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1146\/annurev.bioeng.1.1.241","article-title":"Transport of Molecules, Particles, and Cells in Solid Tumors","volume":"1","author":"Jain","year":"1999","journal-title":"Annu. 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