Defect-Engineered BiO_2-X Nanosheets Mediate Sono-Thermomechanical ECM Remodeling for Hepatocellular Carcinoma Immunotherapy.

Authors

Huimin Tian, Shen Zhang, Bolin Wu, Yichi Chen, Haitao Shang, Haoyan Tan, Chunyue Wang, Weichen Xu, Huixiong Xu, Haohao Yin, Wen Cheng

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77337. Aug 29, 2026. Epub Aug 29, 2026.

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 BiO_2-X nanosheets loaded with Fn1-targeted small interfering RNA (BiO_2-X/siFn1). Introducing oxygen vacancies into ultrathin BiO_2-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 BiO_2-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.

PMID:
42666071
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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