O2-supplementing photosensitizer AuNCs@TAT as a highly efficient NIR-II-controllable pyroptosis inducer for cancer photoimmunotherapy

Pyroptosis resulted from photodynamic therapy (PDT) plays a crucial role in triggering photoimmunotherapy (PIT). However, visible light-triggered PDT may rise phototoxicity, with low penetration into biological tissues. Crucially, the efficacy of PDT in eliciting pyroptosis remains suboptimal. To address these formidable challenges, we developed a O 2 -supplementing photosensitizer AuNCs@TAT that could efficiently induce pyroptosis upon irradiation with second near-infrared (NIR-II) light in hypoxic tumor microenvironment (TME). Replacing GSH with TAT resulted in a gold nanocluster AuNCs@TAT. The ratio of Au (I) to Au (0) shifted from 1: 0.26 in pristine AuNCs to 1: 1.21 in AuNCs@TAT, which contributed to enhanced catalytic activity of AuNCs@TAT. The superior catalase-like activity of AuNCs@TAT produced 1.9-fold higher O 2 than AuNCs. This O 2 self-supplying capability of AuNCs@TAT not only relieved hypoxic condition in TME but also significantly enhanced the efficiency of AuNCs@TAT to induce pyroptosis upon 1064 nm light irradiation. Western blotting indicated both remarkable upregulation of cleft Caspase-3 and GSDME-N, suggesting GSDME mediated pyroptosis. Further, release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs) triggered a strong systematic immune response and reprogrammed the immunosuppressive microenvironment into an immunostimulatory state, which led to a significant suppress of tumor metastasis in mice. Overall, this work sets the stage for future advancements in the design of NIR-II photosensitizer with O 2 -supplementing capability and therefore offers an innovative framework and solid foundation for tumor PIT.