Fe-MnO2 nanosheets loading dihydroartemisinin for ferroptosis and immunotherapy

Background: Hepatocellular carcinoma (HCC) seriously threatens human health and life due to its high mortality. Ferroptosis is an emerging therapeutic based on accumulating the abnormal reactive oxygen species (ROS) of cancer cells. However, the therapeutic effect of a single treatment modality is often limited. A combination therapy of ferroptosis and immunotherapy has shown excellent therapeutic efficacy and is widely used for the treatment of cancer. Here, we designed a nanodrug that loaded DHA on Fe 3+ -doped MnO 2 nanosheets (Fe-MnO 2 /DHA) to treat HCC. Results: : Fe-MnO 2 /DHA would degrade by the glutathione (GSH) of immunosuppressive tumor microenvironment (TME) to release Fe 2+ , Mn 2+ and DHA, leading to ROS accumulation because of Fenton/Fenton-like reaction and breakage of endoperoxide bridge from dihydroartemisinin (DHA) to amplify oxidative stress. Meanwhile, depleting GSH promoted the inactivation of glutathione peroxidase 4 (GPX4), resulting in lipid peroxide (LPO) accumulation. The resulting LPO and ROS induce ferroptosis and apoptosis of liver cancer cells. Consequently, Fe-MnO 2 /DHA three-pronged stimulation activates oxidative stress, resulting in high levels of targeted ICD. It could enhance the infiltration of CD4 + T and CD8 + T cells as well as promote macrophage polarization. DHA also acted as an immunomodulator to inhibit regulatory T cells (Tregs) for systemic antitumor. Conclusion: Fe-MnO 2 /DHA presents a multimodal therapy for HCC driven by ferroptosis, apoptosis and immune activation, significantly advancing synergistic cancer treatment of HCC. The designed nanodrug can act as a promising platform for HCC treatment.