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Войти в исследования Theranostics · 2026
Triple glutathione depletion-augmented disulfide and lipid peroxide accumulation to potentiate disulfidptosis and ferroptosis.
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Du Shulin, Zhang Moyi, Zheng Hao, Gao Ran, Chen Jinrong, Lin Rouyu, Li Jing, Zhang Mengsi, Zhang Hao
Аннотация
UNLABELLED: The adaptive regulation of abnormal redox homeostasis endows tumor cells with robust survival capabilities, with glutathione (GSH) serving as one of the antioxidant cornerstones, which significantly impairs the efficacy of many regulated cell death-related therapies, including disulfidptosis and ferroptosis.
METHODS: Herein, Au nanodot-loaded iron-dithiodiglycolic acid (SS) nanoparticles (FeSS@Au NPs) were engineered to potentiate disulfidptosis and ferroptosis via triple GSH depletion for oncotherapy. FeSS NPs were pre-prepared by dominant coordination-driven self-assembly between FeCl3 and SS. FeSS@Au NPs were prepared through the in situ growth of Au nanodots on FeSS NPs. FeSS@Au NPs were systematically evaluated, including the structure, characteristics, stability and antitumor activity.
RESULTS: Fe3+ in FeSS@Au NPs can oxidize GSH into glutathione (GSSG) through redox reaction. SS can deplete GSH through thiol-disulfide exchange. Au nanodots can disrupt cystine-to-cysteine transformation by attenuating nicotinamide adenine dinucleotide phosphate supplement with its glucose oxidase-like activity, thus downregulating GSH synthesis by providing less cysteine. Resulting from GSH depletion, the accumulated disulfides, including GSSG and cystine, can trigger disulfidptosis. Meanwhile, the inhibited glutathione peroxidase 4 activity and elevated ·OH via Fenton reaction can promote lipid peroxide accumulation, thereby boosting ferroptosis.
CONCLUSIONS: Through a triple GSH depletion strategy, FeSS@Au NPs achieve robust tumor growth inhibition by inducing disulfidptosis and ferroptosis, providing a promising therapeutic approach for efficient tumor treatments.
METHODS: Herein, Au nanodot-loaded iron-dithiodiglycolic acid (SS) nanoparticles (FeSS@Au NPs) were engineered to potentiate disulfidptosis and ferroptosis via triple GSH depletion for oncotherapy. FeSS NPs were pre-prepared by dominant coordination-driven self-assembly between FeCl3 and SS. FeSS@Au NPs were prepared through the in situ growth of Au nanodots on FeSS NPs. FeSS@Au NPs were systematically evaluated, including the structure, characteristics, stability and antitumor activity.
RESULTS: Fe3+ in FeSS@Au NPs can oxidize GSH into glutathione (GSSG) through redox reaction. SS can deplete GSH through thiol-disulfide exchange. Au nanodots can disrupt cystine-to-cysteine transformation by attenuating nicotinamide adenine dinucleotide phosphate supplement with its glucose oxidase-like activity, thus downregulating GSH synthesis by providing less cysteine. Resulting from GSH depletion, the accumulated disulfides, including GSSG and cystine, can trigger disulfidptosis. Meanwhile, the inhibited glutathione peroxidase 4 activity and elevated ·OH via Fenton reaction can promote lipid peroxide accumulation, thereby boosting ferroptosis.
CONCLUSIONS: Through a triple GSH depletion strategy, FeSS@Au NPs achieve robust tumor growth inhibition by inducing disulfidptosis and ferroptosis, providing a promising therapeutic approach for efficient tumor treatments.