Subcellular Targeting and Pyroptosis Activation of Aggregation‐Induced Emission Photosensitizers for Enhancing Photodynamic Therapy of Oral Cancers

Abstract Photodynamic therapy (PDT) is a highly effective strategy for tumor ablation, relying on photosensitizers (PSs) to generate reactive oxygen species (ROS) under light irradiation, which induces cancer cell death. However, the influence of PS subcellular targeting on the efficiency of tumor ablation remains poorly understood. To address this, three aggregation‐induced emission luminogens (AIEgens) with distinct organelle‐targeting capabilities are designed and systematically investigated. Among these PSs, the mitochondria‐targeted MeOTFPy and lysosome‐targeted TPE‐TFPy are found to produce higher levels of ROS in solution and in vitro compared to the cell membrane‐targeted MeOTFVP. Furthermore, the mitochondria‐targeted MeOTFPy demonstrates superior ablation capability of oral cancers, primarily due to its ability to induce mitochondria dysfunction and subsequent pyroptosis activation. Such enhanced therapeutic effect highlights the critical role of mitochondria in ROS‐mediated cell death pathways. This study underscores the significance of subcellular targeting in the design of PSs and offers a promising avenue for improving cancer treatment strategies through pyroptosis.