In Situ Synthesis of Covalent Organic Frameworks Inside Cells for Triggering Ferroptosis and Immunotherapy

The synthesis of non-natural polymers inside living systems has become an effective approach for controlling cellular functions and behaviors. However, in situ synthesis of crystalline polymers, such as covalent organic frameworks (COFs), inside cells using dynamic covalent chemistry faces challenges in aqueous environments, crystallization, and functionality. Herein, we present an intralysosomal crystalline polymerization strategy to synthesize COFs inside tumor cells through an acid-catalyzed imine condensation reaction. The COFs synthesized intracellularly exhibit inherent fluorescence and well-defined crystalline structures, allowing real-time monitoring of the synthesis and product characterization. The formation of imine frameworks inside cell lysosomes induces lysosomal damage, activates lysosomal iron, and triggers immunogenic ferroptosis, thus enhancing antitumor immunotherapy. This strategy of intralysosomal crystalline polymerization facilitates the ambient synthesis of COFs, opening avenues for therapeutic polymerization reactions and providing insights into cellular responses to in situ polymer synthesis.