Glutathione‐Driven Disassembly of Planar Organic Phototherapeutic Agents to Enhance Photodynamic‐Photothermal Therapy Performance for Nasopharyngeal Carcinoma

The self-assembly of hydrophobic organic phototherapeutic agents (OPTAs) with expansive planar structures into nanoparticles (NPs) represents a pivotal strategy to bolster their biocompatibility. However, the tight molecular packing within these NPs significantly influences the generation of reactive oxygen species (ROS) and the photothermal conversion efficiency (PCE), posing a substantial hurdle to elevating the efficacy of photodynamic therapy (PDT) and photothermal therapy (PTT) for such NPs. In this article, three OPTAs by donor engineering are synthesized. Notably, 4,8-Bis (5-phenylthiophen-2-yl)-6-(2-ethylhexyl)-[1,2,5] thiadiazole [3,4-F] benzotriazole (BTBT), which incorporates a benzene ring as the donor, exhibits the highest ROS generation and optimal photothermal conversion capability. To further augment the overall phototheranostic potential of BTBT NPs, a glutathione (GSH)-driven disassembly strategy is employed. This strategy not only alleviates the aggregation-caused quenching (ACQ) effect on ROS but also facilitates enhanced free molecular rotation. As a result, the ROS production sees a tenfold increase, and the photothermal conversion temperature rises by 8.3 °C, achieving a PCE of 77.03%. In summary, a versatile disassembly strategy is proposed that concurrently enhances the performance of both PDT and PTT in planar OPTAs, while also advancing the state-of-the-art in nasopharyngeal carcinoma (NPC) treatment.