Lactate-Fueled TheranosticNanoplatforms for EnhancedMRI-Guided Ferroptosis Synergistic with Immunotherapy of HepatocellularCarcinoma

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 NP_S 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.