Defect-Engineered BiO2-X Nanosheets Mediate Sono-Thermomechanical ECM Remodeling for Hepatocellular Carcinoma Immunotherapy.

Immune checkpoint blockade for hepatocellular carcinoma (HCC) is frequently limited by the extracellular matrix (ECM). Through transcriptomic profiling, we identify that acquired anti-PD-1 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-responsive nanoplatform utilizing oxygen-defect-abundant 2D BiO2-X nanosheets loaded with Fn1-targeted small interfering RNA (BiO2-X/siFn1). Introducing oxygen vacancies into ultrathin BiO2-X alters its band structure, enhancing sono-thermomechanical energy conversion under localized acoustic excitation. This synchronized sono-thermomechanical effect physically remodels the dense collagen matrix, enhancing intratumoral permeation and spatially facilitating immune cell infiltration without relying on extreme hyperthermia. Concurrently, sonothermal-sonomechanical synergistic enhancement of intracellular delivery of siFn1 efficiently downregulates Fn1 expression. This genetic intervention deprives detached tumor cells of integrin-mediated focal adhesion survival signals, resensitizing them to anoikis and effectively suppressing ECM-associated pulmonary metastasis. The BiO2-X/siFn1 nanoplatform significantly increased the recruitment of CD8+ T cells in tumors and restored the therapeutic effect of inhibiting PD-1 in HCC by combining macroscopic physical ECM remodeling with precise molecular blocking of mechanical conduction pathways. This defect-engineered sonosensitization strategy modulates the solid tumor microenvironment and overcomes mechanically induced immunotherapy resistance.