Reprogrammed glycolysis-induced augmentation of NIR-II excited photodynamic/photothermal therapy

Small molecule-based multifunctional optical diagnostic materials have garnered considerable interest due to their highly customizable structures, tunable excited-state properties, and remarkable biocompatibility. We herein report the synthesis of a multifaceted photosensitizer, PPQ-CTPA, which exhibits exceptional efficacy in generating Type I reactive oxygen species (ROS) and thermal energy under near-infrared-II (NIR-II, >1000 nm) laser excitation at 1064 nm, thereby combining photodynamic therapy (PDT) and photothermal therapy (PTT) functionalities. To enhance therapeutic efficacy, we engineered lonidamine (LND) by conjugating it with triphenylphosphonium (TPP) cations, producing LND-TPP. This compound inhibits mitochondrial glycolysis and downregulates heat shock protein 90 (HSP 90) levels in a breast cancer mouse model, potentiating both PDT and PTT. For in vivo applications, PPQ-CTPA and LND-TPP are encapsulated within the amphiphilic polymer DSPE-SS-PEG to obtain PPQ-CTPAL NPs. In breast cancer cell lines, PPQ-CTPAL NPs are decomposed by cellular GSH, simultaneously releasing the dual-functioning photosensitizer PPQ-CTPL and the mitochondria-disrupting agent LND-TPP. Upon 1064 nm laser irradiation, we found that tumor growth in breast cancer mice is effectively restrained by PPQ-CTPAL NPs. This work highlights the synergistic integration of PDT, PTT, and chemotherapy facilitated by NIR-II fluorescence, photoacoustic, and photothermal imaging under 1064 nm irradiation, underscoring the clinical potential of multifunctional phototherapeutic agents.