Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification.

Ferroptosis has been considered as a promising pathway to overcome apoptosis-induced tumor chemoresistance. However, the antitumor efficacy of ferroptosis-inducing agents is still limited because of the complexity and diversity of tumor microenvironments. Herein, we demonstrate a triple ferroptosis amplification strategy for tumor therapy by associating iron-based nanocarriers, ferroptosis molecular drugs, and H 2 O 2 -producing enzymes. Fe(III)-Shikonin (FeShik) metal-polyphenol-coordinated networks are employed to load a ferroptosis inducer of sorafenib (SRF) inside and glucose oxidase (GOx) outside, thus producing SRF@FeShik-GOx supramolecular nanomedicines (SNs). After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe 2+ to induce cell death via ferroptosis. At the same time, GOx executes its catalytic activity to produce an acid environment and plenty of H 2 O 2 for stimulating • OH generation via the Fenton reaction. Moreover, SRF will suppress the biosynthesis of GSH by inhibiting system Xc - , further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4). Up-regulation of the oxidative stress level and down-regulation of GPX4 expression can dramatically accelerate the accumulation of lethal lipid peroxides, leading to ferroptosis amplification of tumor cells. The current strategy that utilizes ferroptosis-inducing agents as both nanocarriers and cargoes provides a pathway to enhance the efficacy of ferroptosis-based tumor therapy.