Electron acceptor motif-manipulated NIR-II AIE photosensitizers synergically induce tumor pyroptosis through multimodal image-guided pure type I photodynamic and photothermal therapy.

Pyroptosis, a form of programmed cell death, is known for its strong capacity to induce immunogenic cell death (ICD), triggering the release of damage-associated molecular patterns (DAMPs) that amplify cancer immunotherapy. Recently, photocontrolled pyroptosis has emerged as a promising strategy within photodynamic therapy (PDT). Nonetheless, most existing photosensitizers exhibit a reliance on both type I and type II reactive oxygen species (ROS) generation, which not only leads to suboptimal efficacy in hypoxic tumor environments but also limits therapeutic depth and selectivity. In this study, we report a lysosome-targeted aggregation-induced emission (AIE) photosensitizer, PTQ-TPA3, engineered through receptor unit loop fusion and rotor integration via molecular evolution strategies. PTQ-TPA3 uniquely achieves highly efficient pure type I ROS generation, alongside near-infrared-II (NIR-II) fluorescence emission and photothermal conversion properties. Under the guidance of multimodal imaging modalities, including photoacoustic, NIR-II fluorescence, and photothermal imaging, PTQ-TPA3 nanoparticles enable synergistic photodynamic and photothermal therapy to drive robust ICD-mediated phototherapy. Furthermore, PTQ-TPA3 demonstrates exceptional efficacy in hypoxic tumor environments by producing pure type I ROS while leveraging its photothermal effect to induce pyroptosis. This dual mechanism effectively eradicates cancer cells and stimulates systemic antitumor immunity, paving the way for innovative therapeutic strategies.