Injectable heavy-atom-free photosensitizer platform for near-infrared activated synergistic photoimmunotherapy

Heavy-atom-free photosensitizers (PSs) have gained attention in tumor photodynamic therapy (PDT) due to their excellent biocompatibility and lack of heavy metal toxicity. This study introduces a new PS molecule:C₈OTTP, encapsulated with DSPE-PEG2000 to form C₈OTTP@NPs, and combined with Raddeanin A (RA) in an ultra-low-temperature agarose hydrogel to create an injectable, light-responsive drug delivery system (named CRH). Upon 808 nm near-infrared light exposure, CRH converts the laser energy into heat due to its excellent photothermal conversion efficiency, dissolving the agarose and releasing RA. Concurrently, photoactivated CRH initiates type I and II PDT reactions, generating reactive oxygen species (ROS) to induce tumor cell apoptosis. The synergistic interaction between RA and ROS generated by PDT markedly enhances the immunogenic cell death (ICD) of tumors. This process involves the release of damage-associated molecular patterns (DAMPs), which activate the intracellular cGAS-STING signaling pathway. Consequently, this activation facilitates the maturation of dendritic cells and enhances tumor antigen presentation. Ultimately, antigen-specific T cells infiltrate the tumor microenvironment, resulting in multi-dimensional immune activation. Experimental findings demonstrate that this combined therapeutic strategy significantly augments the targeting and systemic anti-tumor immune response in cancer treatment through a triple synergy mechanism involving photothermal, photodynamic, and immunomodulatory effects.