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