Molecular Rotor-Based NIR-II TICTgens for Mitochondria-Targeted Pyroptosis Induction and Multi-Model Monitoring of Cancer Immunotherapy

Pyroptosis has emerged as a promising mechanism for eliciting robust antitumor immunity; however, the current pyroptosis inducers lack tumor-selectivity and feedback of therapeutic effect. In this study, we developed a series of twisted intramolecular charge transfer luminogens (TICTgens) for precisely regulating and in situ monitoring of tumor cell pyroptosis in vitro and in vivo. The outperformed TICTgen HCM displayed second near-infrared (NIR-II) fluorescence emission and exceptional viscosity sensitivity. Upon 671 nm laser irradiation, HCM induced the generation of type-I/II reactive oxygen species (ROS) and hyperthermia effect, which cumulatively triggered mitochondrial damage and pyroptosis of tumor cells. HCM was systemically delivered via intracellular acidity-sensitive nanoparticles (namely PDPA@HCM NPs) to effectively trigger pyroptosis-driven antitumor immunity. Notably, HCM performed NIR-II fluorescence and photoacoustic (PA) imaging of pyroptosis-induced mitochondrial dysfunction by measuring viscosity change, thus enabling in situ monitoring of pyroptosis-mediated antitumor immunotherapy. In combination with immune checkpoint blockade therapy, the PDPA@HCM NPs dramatically regressed colorectal tumor growth in a mouse model. Overall, this study demonstrated that the TICTgens could serve as a versatile platform for pyroptosis induction and monitoring of pyroptosis-based cancer immunotherapy.