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, N, N -diphenyl-4-(7-(pyridin-4-yl)benzo[ c ][1,2,5]thiadiazol-4-yl)aniline (TBP + ), were synthesized with different counterions: iodide (I – ), hexafluorophosphate (PF 6 – ), and tetraphenylborate (PhB – ). Among them, TBP-PhB 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, TBP-PhB demonstrated good photodynamic therapy efficacy under hypoxic tumor conditions. Additionally, TBP-PhB 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 TBP-PhB 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.