Sensitizing cuproptosis by endogenous copper-triggered bioorthogonal nanoremodeler

Cuproptosis, a copper-dependent cell death modality identified recently, provides a new avenue for tumor treatment. However, the direct delivery of copper may disturb copper homeostasis of normal tissues and cause side effects. In addition, the metabolic reprogramming of cancer cells and intracellular environment-related biosynthesis of iron-sulfur (Fe-S) cluster proteins severely restrict their sensitivity to cuproptosis. Herein, we construct an endogenous copper-triggered bioorthogonal nanoremodeler for efficient sensitization of cuproptosis. The cell-membrane-coated nanoagent enables the targeted delivery of copper ionophore disulfiram to cancer cells, initiating cell cuproptosis using endogenous copper. Furthermore, endogenous copper-catalyzed bioorthogonal reaction generates glycolytic inhibitor in situ at tumor sites, leading to remodeling of tumor metabolic patterns. Meanwhile, the system reduces the level of iron-sulfur cluster proteins through GSH depletion and oxygen production. The cooperative glycolysis inhibition and intracellular environment remodeling significantly increase the sensitivity of tumor cells to cuproptosis, thereby further enhancing the therapeutic outcome of cuproptosis. The work provides a promising strategy for developing safe and efficient cuproptosis-based tumor treatment.