Tumor-Directed Disulfidptosis via Spatiotemporally Controlled Copper Bioorthogonal Activation

Disulfidptosis, a recently discovered programmed cell death pathway, represents a promising therapeutic strategy for tumors, as its key modulator SLC7A11 is frequently overexpressed in tumor cells. However, inducing disulfidptosis selectively in tumor cells remains a challenge. In this study, we employed a copper-triggered bioorthogonal reaction to generate disulfidptosis agents, specifically in tumor cells. To achieve this goal, rhein-alkyne was encapsulated in ferritin, a tumor-targeting protein cage, in the form of a copper complex (Cu/rhein). With the cotreatment of a ruthenium complex azido-Ru-arene (Ru-N₃), the Cu(I)-catalyzed azide-alkyne cycloaddition generates the cytotoxic product Ru-rhein in tumor cells. Ru-rhein induces disulfidptosis by downregulating glucose transporter 1 (GLUT1), which significantly decreases glucose and NADPH levels in tumor cells, resulting in aberrant accumulation of disulfide bonds and triggering of disulfidptosis. Meanwhile, the accumulation of copper ions from Cu/rhein promotes cuproptosis of tumor cells, further intensifying the disulfidptosis. The <i>in vivo</i> therapeutic effect of the bioorthogonal reactions has been confirmed in tumor-bearing mice. This work offers a therapeutic strategy by introducing copper-triggered bioorthogonal reactions to trigger disulfidptosis and cuproptosis, specifically, in tumors.