Dual-Pronged Light-Free Photodynamic Immunotherapy Enabled by a Chemiexcited Hydrogel.

While singlet oxygen (1O2)-based therapies like photodynamic therapy (PDT) demonstrate clinical anticancer efficacy, their dependence on external light and substantial O2 consumption significantly limits their broader application. To surmount these constraints, we develop a chemiexcited (light-independent) PDT platform by encapsulating bis[2,4,5-trichloro-6-(pentyloxycarbonyl) phenyl] oxalate (CPPO) and chlorin e6 (Ce6) within the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-ethyleneglycol)-2000] (ammonium salt) (DSPE-PEG2000-OMe) micelle (termed CCM). The CCM is then incorporated along with vitamin C (Vc) into a Ca2+-alginate hydrogel, forming a final product denoted as CCMVH. Following intratumoral injection of CCMVH, the sustained Vc release continuously elevates the tumoral H2O2 level. Subsequent reaction of H2O2 with CPPO generates chemical energy, activating Ce6 to produce 1O2 without light. More importantly, we employ hyperbaric oxygen (HBO) to sustain the high intratumoral O2 level during chemiexcited PDT. The synergy between Vc-driven H2O2 generation and HBO-mediated O2 supply creates a dual-pronged amplification effect that significantly enhances 1O2 production. In addition, this light-independent PDT induces marked immunogenic cell death, promotes the infiltration of antitumor immune cells, and reprograms the immunosuppressive tumor microenvironment, resulting in potent tumor inhibition. This work provides a facile strategy for overcoming the fundamental limitations of conventional PDT, offering a translatable approach for cancer immunotherapy.