Lactate-Fueled Theranostic Nanoplatforms for Enhanced MRI-Guided Ferroptosis Synergistic with Immunotherapy of Hepatocellular Carcinoma

Treatment for hepatocellular carcinoma (HCC) may be improved with ferroptosis, a regulated form of cell death. However, the sensitivity of HCC to ferroptosis was strongly limited by lactic acid. In this study, a platelet membrane (PM)-engineered nanoparticle loaded with erastin, superparamagnetic iron oxide nanoparticles (SPIO) and lactate oxidase (LOX) (termed PM@ESL NPs) was designed for magnetic resonance imaging (MRI)-guided enhanced ferroptosis-immunotherapy of HCC. It was found that PM@ESL NPs could actively accumulate into the tumor due to the tumor-homing ability of PM. Subsequently, PM@ESL NPs could effectively enhance the sensitivity of HCC to ferroptosis by removing the lactic acid in the tumor. The removal of lactic acid also produces hydrogen peroxide (H2O2), which therefore converted into the cytotoxic hydroxyl radicals by the reaction of H2O2 with Fe2+/Fe3+ released from SPIO. Due to the combined ferroptosis and chemodynamic therapy (CDT), PM@ESL NPS showed a strong ability to induce immunogenic cell death (ICD), which could effectively suppress the growth and metastasis of HCC when combined with αPD-L1 immunotherapy. Furthermore, the incorporation of SPIO endows PM@ESL NPs with an outstanding MRI-T2 monitoring capability for HCC treatment. In conclusion, this study introduces a pioneering MRI-guided approach that enhances ferroptosis in tumors and synergistically improves immunotherapy.