Multifunctional nanolocks with GSH as the key for synergistic ferroptosis and anti-chemotherapeutic resistance.

The emergence of chemotherapeutic resistance, which is closely related to the oxidative stress defense induced by the imbalance of reactive oxygen species (ROS), is one of the important reasons for the failure of anti-tumor therapy. Herein, a GSH-triggered ferroptosis/apoptosis integrated tumor therapy strategy was successfully implemented to prohibit the mitoxantrone (MTO) resistance. Owing to the overexpressed GSH in the tumor microenvironment, the tumor active targeting MTO-Cu(Ⅱ)-cRGD nanolocks could be dissociated to release Cu(Ⅰ) and MTO, which could persistently catalyze hydrogen peroxide into hydroxyl radicals (•OH) via Fenton-like reaction and generate photothermal effect, respectively. The depletion of GSH inactivated GPX4 for the accumulation of lipid peroxides (LPO) and inducing ferroptosis. With the destruction of oxidative stress defenses, the formation of chemotherapeutic resistance could be effectively prohibited. The nanolocks could eliminate the solid tumors through ferroptosis-sensitized chemotherapy under the guidance of photoacoustic imaging. The study proposed the mechanism of reversing chemotherapeutic resistance by ferroptosis, providing a feasible strategy for the treatment of drug-resistant tumors.