Fe-MnO₂ nanosheets loading dihydroartemisinin for ferroptosis and immunotherapy

Ferroptosis has emerged as a therapeutic tactic to trigger cancer cell death driven by abnormal accumulation of reactive oxygen species (ROS). However, a single ferroptosis treatment modality is often limited. In this work, a combination therapy of ferroptosis and immunotherapy for cancer was proposed. Specifically, a versatile nanodrug was designed for the multiple treatment of hepatocellular carcinoma (HCC) by loading dihydroartemisinin (DHA) on Fe³⁺-doped MnO₂ nanosheets (Fe-MnO₂/DHA). Firstly, Fe-MnO₂/DHA was degraded by glutathione (GSH) in the tumor microenvironment (TME) to release Fe²⁺, Mn²⁺ and DHA, leading to aberrant ROS accumulation due to Fenton/Fenton-like reaction. Secondly, breakage of endoperoxide bridge from DHA was caused by Fe²⁺ to further induce oxidative stress. Thirdly, the depleted GSH promoted the inactivation of glutathione peroxidase 4 (GPX4), resulting in lipid peroxide (LPO) accumulation. The resulting LPO and ROS could induce ferroptosis and apoptosis of liver cancer cells. Furthermore, Fe-MnO₂/DHA mediated three-pronged stimulation of oxidative stress, resulting in high levels of targeted immunogenic cell death (ICD). It could enhance the infiltration of CD4⁺ T and CD8⁺ T cells, and promote macrophage polarization. DHA also acted as an immunomodulator to inhibit regulatory T cells (Tregs) for systemic antitumor. Overall, Fe-MnO₂/DHA presents a multi-modal therapy for HCC driven by ferroptosis, apoptosis and immune activation, significantly advancing synergistic cancer treatment.