Thiazolo[5,4-d]thiazole π-bridge engineering of AIE photosensitizers toward mitochondria-localized photodynamic therapy.

Aggregation-induced emission (AIE) photosensitizers have emerged as promising candidates for photodynamic therapy (PDT) because they can overcome aggregation-caused quenching and retain strong fluorescence in biological environments. However, rational π-bridge engineering for simultaneously optimizing photophysical properties and reactive oxygen species (ROS) generation remains insufficiently explored. Herein, we report a series of thiazolo[5,4-d]thiazole (TzTz)-bridged AIE photosensitizers constructed within donor-π-acceptor frameworks. The rigid and electron-deficient TzTz unit, together with donor strengthening and acceptor cationization, modulates the electronic structures of the molecules, enhances intramolecular charge transfer, and contributes to ROS-generating capability. Among the synthesized compounds, MTPA-TzTz-TPP exhibited pronounced AIE characteristics with strong red fluorescence emission at 641 nm in the aggregated state and efficient light-triggered ROS generation. Confocal imaging demonstrated that MTPA-TzTz-TPP selectively accumulated in mitochondria, showing a Pearson's correlation coefficient of 0.84 with the mitochondrial tracker. In vitro studies showed that MTPA-TzTz-TPP possessed minimal dark toxicity but significant phototoxicity toward 4 T1 tumor cells, accompanied by a marked intracellular ROS burst and effective light-induced cell death. Furthermore, intratumoral administration of MTPA-TzTz-TPP in a 4 T1 tumor-bearing mouse model led to pronounced tumor growth inhibition under light irradiation without obvious systemic toxicity. This work highlights TzTz π-bridge engineering as an effective molecular design strategy for developing high-performance AIE photosensitizers and identifies TPP functionalization as an effective approach for achieving mitochondria-localized photodynamic therapy.