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

## TL;DR

Scientists created a method to make special polymers inside cells, which can damage cancer cells and boost immune treatments.

## Contribution

A new intralysosomal crystalline polymerization strategy for COF synthesis inside cells is introduced.

## Key findings

- COFs synthesized in lysosomes cause lysosomal damage and activate iron species.
- The method triggers immunogenic ferroptosis and enhances antitumor immunotherapy.
- Intracellular COFs show fluorescence and crystalline structures for real-time monitoring.

## Abstract

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.

We have developed an intracellular crystalline polymerization strategy involving acid‐catalyzed imine condensation to synthesize COFs in lysosomes. The generation of COFs in lysosomes damages their integrity, activates iron species, and induces immunogenic ferroptosis, thereby enhancing antitumor immunotherapy. This strategy facilitates ambient COF synthesis and provides insight into artificial chemical reactions within biological systems.