Piezocatalytic Nanoplatform Drives Mg²⁺-Release-Amplified Ferroptosis-Immune Synergy for Tumor Microenvironment Reprogramming.

Abstract

The tumor microenvironment (TME) is characterized by immunosuppression, restricting immune activation and T cell infiltration and thereby reducing therapeutic efficacy. Effective TME reprogramming is critical to amplify immune responses and improve therapeutic outcomes. Herein, hyaluronic acid-modified Cu₃BiS₃/MgO₂ nanoparticles (CBS/Mg NPs) are engineered to implement a "shock and awaken" strategy that achieves ultrasound-responsive piezocatalytic therapy (PCT) with Mg²⁺-release-amplified ferroptosis and immunomodulation. Benefiting from the partially degradable design, CBS/Mg NPs possess a self-supplied H₂O₂ capability and release Mg²⁺ in acidic TME, where H₂O₂ fuels a Cu⁺-mediated Fenton-like reaction. Concurrently, under ultrasound irradiation, the piezoelectric Cu₃BiS₃ generates a built-in electric field that efficiently facilitates the separation of electron-hole pairs, thereby amplifying oxidative stress and delivering a piezocatalytic "shock" to tumor cells. The resulting excessive reactive oxygen species accumulation, coupled with glutathione depletion, suppresses GPX4 expression and accelerates lipid peroxidation, ultimately awakening ferroptosis. Ferroptosis-induced immunogenic cell death triggers immune activation, which is further potentiated by Mg²⁺ release. Moreover, activated T cells secrete IFN-γ, which suppresses SLC7A11 expression and reduces intracellular glutathione synthesis, therefore establishing a self-amplifying ferroptosis loop. As envisaged, this "shock and awaken" strategy, integrating PCT with a partially degradable design, effectively reprograms the immunosuppressive TME, improves antitumor efficacy, and inhibits lung metastasis, highlighting its promise for piezocatalytic immunomodulation.