A Peripheral Sulfonium Moiety Engineering Strategy to Enhance AIEgen-Based Antitumor Photodynamic Therapy.

The therapeutic efficacy of photosensitizers (PSs) strongly depends on their capacity to efficiently generate reactive oxygen species (ROS). Herein, we report a peripheral sulfonium moiety engineering strategy and identify a lead aggregation-induced emission (AIE)-based PS, S12. The sulfonium moiety enhances the photosensitization of S12 primarily by increasing spin-orbit coupling (SOC) and reducing ΔEST, thus boosting ROS generation. Moreover, the sulfonium unit enables S12 to simultaneously produce both Type I and Type II ROS, rendering its photosensitization weakly dependent on O2 concentration. Owing to its cationic character and the inherent amphiphilicity of the AIE core, S12 exhibits dynamic organelle-targeting behavior, initially anchoring to membranes and subsequently accumulating in lipid droplets. Such localization facilitates ROS-triggered ferroptosis, leading to potent in vitro antitumor photodynamic therapy activity and effective tumor suppression in a 4T1 mouse model. Overall, this work provides a rational design strategy to advance AIE-based PSs with enhanced therapeutic potential.