Zwitterionic Photosensitizer Triggers Photopyroptosis for Effective Cancer Immunotherapy

Photopyroptosis, a lytic and immunogenic cell death modality triggered by photosensitizer (PS)-generated reactive oxygen species under specific light irradiation, offers a promising strategy to overcome the inherent limitations of conventional cancer therapies. However, the precise design of PSs to induce photopyroptosis under hypoxic tumor microenvironments remains challenging. Herein, we report a zwitterionic nano-photosensitizer (PCBMA-TAPP) that combines mitochondrial-targeted Type I photodynamic therapy (PDT) with enhanced tumor accumulation to potentiate pyroptosis-driven immunotherapy. A comparative evaluation of three porphyrin-based PSs identified tetra (4-aminophenyl) porphyrin (TAPP) as a lead candidate with superior mitochondrial localization and enhanced generation of superoxide anions (•O₂ ^-), enabling potent caspase-3/gasdermin E-mediated pyroptosis. Encapsulation of TAPP into redox-responsive poly (carboxybetaine methacrylate) (PCBMA) nanogels prolongs circulation, enhances passive targeting, and preserves photodynamic activity. In vitro, PCBMA-TAPP rapidly induces plasma membrane disruption, release of lactate dehydrogenase and adenosine triphosphate, and activation of the NLRP3 inflammasome, thereby promoting dendritic cell maturation. In EMT6 tumor-bearing mice, PCBMA-TAPP achieves 84.9% tumor growth inhibition, accompanied by elevated infiltration of CD8⁺, CD4⁺, and granzyme B expression, without observable systemic toxicity. These findings established a nanoplatform that synergizes organelle-specific Type I PDT with pyroptosis-driven immune activation, advancing a clinically translatable strategy for immunotherapy of hypoxic tumors.