Poly(sodium lipoate) Particles with Nitroimidazole Modification for Disulfide Stress-Mediated Antitumor Metastasis

Disulfidptosis, a form of programmed cell death triggered by disulfide stress, holds promise for antimetastatic strategies by promoting cytoskeletal collapse, while no relevant applied study was reported. Herein, we develop a disulfide stress inducer for antitumor metastasis by nitroimidazole-grafted poly(sodium lipoate) nanoparticles (NI@PSL). Upon thiol-mediated cellular uptake, NI@PSL degraded into dihydrolipoic acid (DHLA) and exposed grafted nitroimidazole (NI) in response to glutathione (GSH). DHLA formed aberrant disulfide bonds with cytoskeletal cysteine thiols. NI moieties were reduced to aminoimidazole by hypoxia-activated nitroreductase, resulting in nicotinamide adenine dinucleotide phosphate (NADPH) depletion. This redox imbalance prevented the reduction of intercytoskeletal disulfide bonds, leading to irreversible cytoskeletal collapse and subsequent metastasis inhibition. In vitro assays demonstrated that NI@PSL decreased the migration and invasion rates of highly metastatic B16F10 cells to 12.8 and 7.0%, respectively. In the B16F10 tumor-bearing mice model, NI@PSL nearly eliminated lung and liver metastatic foci. These results provide a strong basis for using disulfide stress to combat tumor metastasis.