Enhanced population of excited single state strategy: irradiation and ultrasound dual-response and host tumor-driven nano-sensitizers construction in triple synergistic therapy

Phototheranostics is an emerging field in synergistic antitumor therapy in which irradiation and sensitizers are combined to produce reactive oxygen species (ROS), bio-images, and high temperatures. All of these are arrived from the energy of sensitizers, which located in excited single state (S1). Undeniably, the decentralization of the S1 population indirectly decreases the effect of each individual treatment. In this study, a strategy was proposed for enhancing the S1 population, and a sensitizer with mitochondrial targeting property, 1,4-indolyl iodinated pyrrolo[3,2-b]pyrrole derivative (2I-TPIS), was assembled into adenosine triphosphate (ATP)-responsive nanoparticles (DPA-2I NPs) to achieve dual responses to irradiation and ultrasonication (US) for application to photo-sonodynamic therapy (PSDT). Compared with monotherapies, 2I-TPIS generated more ROS in PSDT, inducing mitochondrial autophagy and apoptosis, which in turn triggered immunogenic cell death (ICD). Subsequently, DPA-2I NPs were constructed and self-assembled with the chemotherapeutic agents DPA-Cd and 2I-TPIS to achieve a triple synergistic strategy involving chemotherapy (CT) and PSDT. DPA-2I NPs exhibited absolute sensitization, intra-tumoral overexpression of ATP, and disassembly. Importantly, the biosafety and potent antitumor efficiency of the DPA-2I NP-based “PSDT + CT” therapy were revealed using a 4T1 tumor model. The study results provide insights into the design of sensitizers possessing a sufficient S1 population and a highly efficient tumor ablation capacity derived from molecular structural modulation, further enabling triple synergistic antitumor therapies, and expanding the clinical application of sensitizers.