Covalent organic framework eliciting a click-based intracellular copper accumulation cascade for cuproptosis cancer therapy

Cuproptosis therapies hold potential for cancer treatment but need to overcome cancer cell resistance mechanisms against copper accumulation while avoiding systemic toxicity. Here, we report a cuproptosis therapeutic nanosystem (P1+P2@COF@F127-D) utilizing only endogenous copper enriched by cascade accumulation. In cancer cells treated by these nanoparticles, high glutathione (GSH) levels induced DC_AC50 release to inhibit ATOX1 and CCS proteins, increasing intracellular Cu⁺ levels. This promoted a click reaction of prodrug P1 and P2 to form C147, subsequently reducing intracellular GSH levels by 60% in vitro, suppressing the formation of GSH-Cu complexes and further elevating the intracellular Cu⁺ level. Consequently, an 8-fold increase of the free Cu⁺ level was achieved, leading to cuproptosis and copper-induced ferroptosis in cancer cells. In a murine melanoma model, P1+P2@COF@F127-D demonstrated a high antitumor efficacy without showing noticeable systemic toxicity. Collectively, this work elucidates biomedical engineering principles to shift intracellular copper homeostasis to enable cuproptosis and bioorthogonal CuAAC.