Nanospheres of Near-Infrared Aggregation-Induced Emission Probes to Target Mitochondria to Ablate Tumors with Reactive Oxygen Species Generation under Hypoxia

Severe aggregation-caused quenching and the lack of special organelle targeting in conventional photosensitizers (PSs) have limited their advantages in terms of their accurate spatial–temporal control and noninvasive features. Furthermore, severe tumor hypoxia equally diminished the effectiveness of treatment. Herein, a series of aggregation-induced emission (AIE) PSs with precise targeting of organelles are synthesized by simply regulating the molecular structure. The rotation of the donor in the molecule was optimized by altering the tail chain of the triphenylamine derivative, which inhibited nonradiative internal conversion and promoted intersystem crossing to facilitate the free radical generation, and the production efficiency of the type I reactive oxygen species exceeds that of the commercial indicator rose bengal (3-fold). The optimal AIE PS named BETTP can specifically target mitochondria and recognize cancer cells. Simultaneously, live/dead cell costaining assays and flow cytometry validated that BETTP nanoparticles (NPs) have the ability to efficaciously ablate cancer cells in hypoxic conditions after encapsulating BETTP into carriers as nanoparticles. In addition, BETTP NPs also manifest superior performance during near-infrared imaging-guided type I photodynamic therapy in solid tumors. Such BETTP NPs demonstrate the critical feasibility of achieving precise delivery of drugs and targeting of organelles for precise therapy in hypoxic environments, providing a reliable reference for tumor hypoxia challenges.