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Through transcriptomic profiling, we identify that acquired anti\u2010PD\u20101 resistance in HCC models is closely associated with prominent Fibronectin 1 (Fn1) upregulation within the tumor microenvironment. To address these interconnected physical and biological barriers, we developed an ultrasound\u2010responsive nanoplatform utilizing oxygen\u2010defect\u2010abundant 2D BiO\n                    <jats:sub>2\u2010X<\/jats:sub>\n                    nanosheets loaded with Fn1\u2010targeted small interfering RNA (BiO\n                    <jats:sub>2\u2010X<\/jats:sub>\n                    \/siFn1). Introducing oxygen vacancies into ultrathin BiO\n                    <jats:sub>2\u2010X<\/jats:sub>\n                    alters its band structure, enhancing sono\u2010thermomechanical energy conversion under localized acoustic excitation. This synchronized sono\u2010thermomechanical effect physically remodels the dense collagen matrix, enhancing intratumoral permeation and spatially facilitating immune cell infiltration without relying on extreme hyperthermia. Concurrently, sonothermal\u2010sonomechanical synergistic enhancement of intracellular delivery of siFn1 efficiently downregulates Fn1 expression. This genetic intervention deprives detached tumor cells of integrin\u2010mediated focal adhesion survival signals, resensitizing them to anoikis and effectively suppressing ECM\u2010associated pulmonary metastasis. The BiO\n                    <jats:sub>2\u2010X<\/jats:sub>\n                    \/siFn1 nanoplatform significantly increased the recruitment of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in tumors and restored the therapeutic effect of inhibiting PD\u20101 in HCC by combining macroscopic physical ECM remodeling with precise molecular blocking of mechanical conduction pathways. This defect\u2010engineered sonosensitization strategy modulates the solid tumor microenvironment and overcomes mechanically induced immunotherapy resistance.\n                  <\/jats:p>","DOI":"10.1002\/advs.77337","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:10:46Z","timestamp":1787987446000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Defect\u2010Engineered BiO\n                    <sub>2\u2010X<\/sub>\n                    Nanosheets Mediate Sono\u2010Thermomechanical ECM Remodeling for Hepatocellular Carcinoma Immunotherapy"],"prefix":"10.1002","author":[{"given":"Huimin","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Ultrasound Harbin Medical University Cancer Hospital  Harbin Heilongjiang People's Republic of 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