A vinyl-decorated covalent organic framework for ferroptotic cancer therapy via visible-light-triggered cysteine depletion

Biothiols, including glutathione (GSH) and cysteine, are important reductants that maintain intracellular redox homeostasis. Recent studies have demonstrated that cysteine deprivation is a more effective antitumor strategy than GSH depletion. However, the lack of highly chemoselective and tumor-specific cysteine-consuming reagents limits the practical application of cysteine deprivation. Herein, we report a vinyl-decorated nanoscale covalent organic framework (COF) prepared in aqueous solution at room temperature. After encapsulating a Ru(II)-based photocatalyst, the obtained Ru(II)@COF-V efficiently catalyzes the thiol-ene click reaction between vinyl and cysteine upon visible-light irradiation. Ru(II)@COF-V preferentially accumulates in lipid droplets of tumor cells via lipid raft- and caveolin-related endocytosis and induces lipid peroxidation and ferroptosis by consuming cysteine, exhibiting powerful therapeutic activity against colon cancer. We believe that this study both enriches the ambient synthesis of nanoscale COFs and highlights the feasibility of intracellular photochemical reactions for tumor therapy.