Sono-Gas-Mediated Precise Stiffness Remodeling for Triple-Negative Breast Cancer Mechanical Immunotherapy

Triple-negative breast cancer (TNBC) is a highly invasive cancer, and its poor therapeutic outcomes are often associated with the mechanical properties of the tumor microenvironment, which is characterized by altered extracellular matrix (ECM) flexibility and increased stiffness. Herein, a mechanical immunomodulator, namely, red blood cell membrane-IR780-L-arginine nanoparticles (R-I-LA NPs), was designed to precisely regulate the stiffness of the ECM for mechanical immunotherapy of TNBC. In tumor cells, the low-intensity focused ultrasound activates R-I-LA NPs to produce reactive nitrogen species, which damages tumor cells and remodels the stiffness of ECM. Meanwhile, the softened ECM can normalize the tumor vasculature to alleviate hypoxia and increase the production of reactive oxygen species, thereby enhancing the efficacy of sonodynamic therapy and stimulating immunogenic cell death. Additionally, R-I-LA NPs stimulate the immune system and suppress pulmonary metastasis. Overall, this study offers a distinctive “sono-gas-mediated mechanical immunity” strategy for ECM regulation, potentially overcoming current TNBC therapy limitations.