Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy

Nowadays, destruction of redox homeostasis to induce cancer cell death is an emerging anti-cancer strategy. Here, the authors utilized pH-sensitive acetalated β-cyclodextrin (Ac-β-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-β-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe 2+ /Fe 3+ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H 2 O 2 ), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the O  O bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. Their results demonstrate that these nanoparticles acted as a ROS generator to break the redox balance of cancer cells, showing an effective anticancer efficacy, which is different from traditional approaches.