Enhanced population of excited single state strategy:Irradiation and ultrasound dual-response and host tumor-driven nanosensitizers 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(S_(1)).Undeniably,the decentralization of the S_(1)population indirectly decreases the effect of each individual treatment.In this study,a strategy was proposed for enhancing the S_(1)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 S_(1)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.