Abstract
The development of efficient therapeutic strategies to promote ferroptotic cell death offers significant potential for hepatocellular carcinoma (HCC) treatment. Herein, this study presents an HCC-targeted nanoplatform that integrates bimetallic FeMoO4 nanoparticles with CO-releasing molecules, and further camouflaged with SP94 peptide-modified macrophage membrane for enhanced ferroptosis-driven multi-modal therapy of HCC. Leveraging the multi-enzyme activities of the multivalent metallic elements, the nanoplatform not only decomposes H2O2 to generate oxygen and alleviate tumor hypoxia but also depletes glutathione to inactivate glutathione peroxides 4, which amplify sonodynamic therapy and ferroptotic tumor death under ultrasound (US) irradiation. Meanwhile, the nanoplatform catalyzes the Fenton reaction to produce hydroxyl radicals for chemodynamic therapy. Elevated intracellular reactive oxygen species trigger the cascade release of CO, leading to lethal lipid peroxidation and further enhancing ferroptosis-mediated tumor therapy. This nanoplatform demonstrates robust anti-tumor efficacy under US irradiation with favorable biosafety in both subcutaneous and orthotopic HCC models, representing a promising therapeutic approach for HCC. Additionally, the findings offer new insights into tumor microenvironment modulation to optimize US-triggered multi-modal cancer therapy.