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

Abstract 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.