H2S and NIR light-driven nanomotors induce disulfidptosis for targeted anticancer therapy by enhancing disruption of tumor metabolic symbiosis

Disulfidptosis, a novel mechanism of programmed cell death through the disruption of tumor metabolic symbiosis (TMS), has showed tremendous potential in cancer therapy. However, the efficacy of disulfidptosis is limited by poor permeability of drugs in solid tumors. Herein, hydrogen sulfide (H₂S) and near-infrared (NIR) light-driven nanomotors (denoted as HGPP) have been constructed to efficiently penetrate tumors and induce disulfidptosis. HGPP demonstrate glutathione (GSH)-responsive release of H₂S, which combined with NIR light-induced photothermal effect drive HGPP movement to facilitate deep tumor penetration. The released H₂S induces tumor acidosis and disrupts TMS, where disulfide accumulation following cell starvation leads to disulfidptosis. In addition, HGPP induce hepatoma specific cellular uptake and catalyze the conversion of glucose and oxygen to produce hydrogen peroxide (H₂O₂), leading to glucose starvation. Overall, this study has developed a multifunctional Janus nanomotor that provides a novel strategy for disulfidptosis-based solid tumor therapy.