Fe-MnO2 nanosheets loading dihydroartemisinin for ferroptosis and immunotherapy
Dandan Huang, Dafen Xu, Wenxin Chen, Ruimei Wu, Yujuan Wen, Ai‐Lin Liu, Liqing Lin, Xinhua Lin, Xuewen Wang
Abstract
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.