Engineering Aggregation-Induced Emission Photosensitizers through a Counterion-Modulation Strategy for Enhanced Photodynamic Immunotherapy

The intersystem crossing (ISC) process of photosensitizers (PSs) is crucial for the generation of reactive oxygen species (ROS) in photodynamic immunotherapy. Herein, a counterion-regulation strategy is applied to enhance ISC efficiency in aggregation-induced emission (AIE) PSs, optimizing type-I ROS production. Three PSs with the same cationic donor-π-acceptor (D-π-A) structure, <i>N</i>,<i>N</i>-diphenyl-4-(7-(pyridin-4-yl)benzo[<i>c</i>][1,2,5]thiadiazol-4-yl)aniline (TBP⁺), were synthesized with different counterions: iodide (I^-), hexafluorophosphate (PF₆^-), and tetraphenylborate (PhB^-). Among them, <b>TBP-PhB</b> exhibits an improved AIE performance and type-I ROS generation. Theoretical calculation revealed that the augmented ROS production stems from increased ISC efficacy, facilitated by additional transition channels with smaller energy gaps and larger spin-orbit coupling values. Meanwhile, <b>TBP-PhB</b> demonstrated good photodynamic therapy efficacy under hypoxic tumor conditions. Additionally, <b>TBP-PhB</b> activated immunogenic cell death, promoted dendritic cell maturation, and stimulated cytotoxic T cells, thereby enhancing immunotherapy. Tumor inhibition was observed in both primary and distant tumors treated with <b>TBP-PhB</b> under light irradiation. Collectively, this work presents an approach to improving type-I ROS in AIE PSs by optimizing the ISC process, highlighting the potential of counterion modulation for developing efficient AIE PSs for advanced photodynamic immunotherapy.