Spatiotemporal organelle delivery and activation of type I AIE photosensitizers and siRNA for near-infrared fluorescence image-guided immunotherapy.

The spatiotemporal delivery and activation of small-molecule drugs and macromolecular biologics at the organelle level for cancer immunotherapy remain a significant challenge. To address this issue, we developed TPR, an all-in-one nanoplatform for mitochondria-targeted photodynamic therapy and PD-L1 gene silencing. TPR is engineered to remain stable in circulation while responding to the acidic tumor microenvironment to release its cargo. The core component, a Type I photosensitizer with aggregation-induced emission (AIE), enables near-infrared fluorescence imaging and induces potent immunogenic cell death via mitochondrial dysfunction upon laser irradiation. Concurrently, the released siRNA silences PD-L1 expression in tumor cells, significantly enhancing the antitumor immune response and resulting in synergistic efficacy against both primary and metastatic tumors. In summary, this research presents an innovative approach that integrates advanced drug delivery systems with synergistic therapeutic modalities, achieving enhanced precision and efficacy in cancer immunotherapy.