Copper-doped COF triggered bioorthogonal synergistic cancer therapy through apoptosis and cuproptosis

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, owing to its high efficiency and selectivity, holds great potential in biomedicine. However, harnessing it for effective tumor-targeted therapy remains challenging. Herein, a copper-doped hollow covalent organic framework-based platform (HCOF@Cu) was developed, and then co-loading two inactive prodrugs that underwent in situ CuAAC reaction within the tumor microenvironment, enabling efficient synthesis of the active anticancer drug to inhibit the tumor growth. Meanwhile, embedded copper ions triggered a cascade reaction that consumed overexpressed intracellular glutathione (GSH) and generated reactive oxygen species (ROS). The resulting redox disruption induced ferredoxin 1 (FDX1) depletion, and oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), ultimately leading to apoptosis. This strategy integrates apoptosis and cuproptosis for synergistic cancer therapy, offering a new avenue for combined cancer treatment.