A H₂O₂-Responsive Polyprodrug Nanomedicine for Chemiexcited Photodynamic Immunotherapy of Cancer

Although chemiexcited photodynamic therapy (CPDT) has garnered significant interest in combating deepseated tumors without the need for external irradiation, the potential of CPDT in antitumor immunotherapy has been rarely explored due to the formation of an immunosuppressive tumor microenvironment (TME). Herein we developed a chlorin e6 (Ce6)-conjugated polyprodrug nanoparticle composed of polymerized hydrogen peroxide (H₂O₂)-responsive NLG919 prodrug monomers to enable synergistic CPDT and immunotherapy, taking advantage of CPDT-induced immunogenic cell death (ICD) and NLG919-mediated IDO-1 suppression to elicit potent antitumor immune responses. The polyprodrug nanoassemblies rapidly dissociate when exposed to abundant H₂O₂ in tumors, leading to the release of NLG919 and the generation of highenergy intermediate dioxetanedione. The latter transfers energy to adjacent Ce6 to activate¹O₂ generation by chemiexcitation and induce ICD of tumor cells, while NLG919 suppresses the activity of intratumoral IDO-1, thus attenuating the immunosuppressive TME and amplifying ICD-induced antitumor immunity. Consequently, the polyprodrug nanomedicine can evoke strong antitumor immune responses to realize effective and long-lasting suppression of tumor growth, recurrence and metastasis without the concern of systemic toxicity, providing a potential antibody-independent platform for chemiexcited photodynamic immunotherapy of cancer.