Dual‐Pronged Light‐Free Photodynamic Immunotherapy Enabled by a Chemiexcited Hydrogel

ABSTRACT

While singlet oxygen ( ¹ O ₂ )‐based therapies like photodynamic therapy (PDT) demonstrate clinical anticancer efficacy, their dependence on external light and substantial O ₂ 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(poly­ethyleneglycol)‐2000] (ammonium salt) (DSPE‐PEG ₂₀₀₀ ‐OMe) micelle (termed CCM). The CCM is then incorporated along with vitamin C (Vc) into a Ca ²⁺ –alginate hydrogel, forming a final product denoted as CCMVH. Following intratumoral injection of CCMVH, the sustained Vc release continuously elevates the tumoral H ₂ O ₂ level. Subsequent reaction of H ₂ O ₂ with CPPO generates chemical energy, activating Ce6 to produce ¹ O ₂ without light. More importantly, we employ hyperbaric oxygen (HBO) to sustain the high intratumoral O ₂ level during chemiexcited PDT. The synergy between Vc‐driven H ₂ O ₂ generation and HBO‐mediated O ₂ supply creates a dual‐pronged amplification effect that significantly enhances ¹ O ₂ 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.