A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin

Abstract Background Chemodynamic therapy (CDT) relying on intracellular iron ions and H 2 O 2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H 2 O 2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H 2 O 2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy. Results The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity. Conclusion In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine. Graphical Abstract