Reactive Oxygen-Primed and Autophagy Inhibition-Sensitized Ferroptosis Combined with Photothermal Ablation for Tumor Therapy

The accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation (LPO) is the hallmark of ferroptosis therapy. However, a single ferroptosis process has difficulty inhibiting tumor progress. Autophagy inhibitors can inhibit autophagy by blocking automatic capsules and closing the self-protection pathway of oxidative stress, which promotes a Fenton or Fenton-like reaction to enhance LPO accumulation. Herein, a versatile core–shell nanoparticle system, denoted as CQ/PEG-CuS@hMnO2, was designed and synthesized for reactive oxygen-primed and autophagy inhibition-sensitized ferroptosis. Glutathione (GSH) depletion by CuS@hMnO2 caused the inactivation of glutathione peroxidase 4 (GPX4), the key defense protein of ferroptosis. Highly toxic ROS were generated by Mn2+-mediated Fenton-like reaction to reinforce the intracellular oxidative stress, directly resulting in the accumulation of LPO. Meanwhile, autophagy played an indispensable effect in ferroptosis; thus, the loading of chloroquine (CQ) as an autophagy inhibitor aimed to enhance the sensitivity of ferroptosis. Besides, the excellent photothermal therapy effect could be triggered by NIR irradiation (980 nm) due to CuS core. In vivo and in vitro experiment results demonstrated that CQ/PEG-CuS@hMnO2 presented an excellent anticancer effect in the human breast cancer model, proving that the ferroptosis/photothermal dual-inductive strategy is promising to combat malignant tumors.