Disruption of self-protection pathways enables endogenous copper-evoked cuproptosis via bioorthogonal nanoblocker

Cuproptosis, a novel form of copper-dependent cell death, exhibits broad prospects in cancer therapy. However, the application of cuproptosis-based tumor therapy still remains challenging due to the inherent self-protection mechanisms of tumor cells, including copper efflux mediated by copper-transporting proteins and copper-induced protective autophagy. Herein, we construct a safe and efficient bioorthogonal nanoblocker, which can disrupt the self-protection pathways to enable endogenous copper-evoked cuproptosis. The gene silencing-mediated blockage of copper efflux leads to the accumulation of endogenous copper, thereby inducing mitochondrial protein aggregation to efficiently trigger cuproptosis. Meanwhile, the bioorthogonal synthesis of an autophagy inhibitor blocks the resistance of cancer cells to copper overload-mediated cuproptosis. The combination of endogenous copper accumulation and tumor self-protection destruction leads to the death of tumor cells with minimal side effects, thereby achieving a safe and effective cuproptosis-based cancer treatment. This work offers a new avenue for developing cuproptosis-based therapeutic strategies by using endogenous copper and overcoming intrinsic self-protection pathways. [Display omitted] •The nanoblocker mitigates the inherent cuproptosis resistance of cancer cells.•Bioorthogonal chemistry manipulates autophagy process of cancer cells in situ.•Endogenous cuproptosis inducer avoids the adverse effects caused by external Cu.