Engineering Ternary PdMop Nanoenzyme for Enzyodynamic Effect-Enhanced Ferroptosis and Sonocatalysis-Enabled Tumor Immunotherapy

Immunotherapy has become one of the most effective therapeutic modalities for achieving long-term cancer remission, but the available immunotherapeutic strategies suffer from modest response rates owing to the insufficient immunogenicity of tumor cells. In this work, a nanomedicine strategy for maintaining highly immunogenic tumor cells by inducing cascade-mediated immunogenic tumor-cell ferroptosis is proposed and developed. A PdMoP nanoplatform is engineered that not only induces initial immunogenic tumor cell ferroptosis through its multienzyme-mimicking activities but also accelerates Mo(IV)-to-Mo(VI) transition, which aggravates glutathione (GSH) depletion for deactivating glutathione peroxidase 4 (GPX4) enzyme and lead to excessive radical production for promoting p53 expression and reducing SLC7A11, thereby resulting in efficient ferroptosis and apoptosis. Additionally, PdMoP nanoparticles induce the breakdown of hydrogen peroxide into oxygen to alleviate tumor hypoxia, working synergistically with GSH depletion to reverse the immunosuppressive tumor microenvironment. Significant ferroptosis (through the classical p53-SLC7A11-GPX4 pathway) is monitored in both in vitro cellular level and in vivo tumor models, achieving effective tumor suppression and elimination. The distinct ultrasound-enhanced enzyodynamic therapy strategy represents a simple and effective paradigm for treating cancer by nanocatalytic medicine and catalytic biomaterials. The ternary PdMoP composite nanoenzymes enable an irreversible cascade of immunogenic tumor cell ferroptosis by promoting reactive oxygen species (ROS) production and GSH/GPX4 depletion and reversing the immunosuppressive tumor microenvironment (TME) for the enzyodynamic effect-enhance ferroptosis and sonocatalysis-enabled tumor immunotherapy of breast cancer. The engineered multicomponent nanoenzymes feature remarkable potential for the clinical treatment of cancer.image