Dual Strategy of Ca²⁺ Influx and Collagen Denaturation to Remodel the Extracellular Matrix and Amplify Sonopiezoelectric Therapy

Extracellular matrix (ECM), a core member of tumor microenvironment, is ≈1.5-fold harder than the surrounding normal tissues. Regulating the stiffness of ECM can significantly impact physiological activities of tumor cells, such as growth, differentiation, and migration. Herein, a sonopiezoelectric-response nanoplatform consisting of Cu₃BiS₃ nanospheres (CBS NSs) is constructed for ECM remodeling. Sonopiezoelectric therapy (SPT) and chemodynamic therapy (CDT) are conducted using ultrasound (US) and near-infrared irradiation. Under US irradiation, the mechanical strain of CBS NSs causes piezoelectric polarization and promotes a redox reaction through energy band bending. The built-in electric field generated by US irradiation amplifies the efficiency of the Fenton-like reaction and substantially enhances reactive oxygen species production. Moreover, piezoelectric property-mediated electrical signals can allow Ca²⁺ influx, upregulating the levels of matrix metalloproteinase (MMP)-2 and MMP-9. Integrating US irradiation with near-infrared irradiation generates localized heat, which can effectively denature tumor collagen, reduce tumor stiffness, and enhance the permeability of CBS NSs into solid tumors, thus improving the SPT effect. The combination of MMP upregulation and collagen degradation can maximize the benefits of ECM remodeling and synergistically enhance the cancer therapeutic efficacy of SPT/CDT. This SPT/CDT synergistic therapy and ECM remodeling platform is an innovative strategy for cancer therapy.