Zwitterionic Nanoplatform-Mediated Photopyroptosis for Abscopal Effect-Enhanced Cancer Immunotherapy

Cancer immunotherapy is limited by weak durable systemic immunity, especially against distant untreated lesions. Pyroptosis is a highly immunogenic programmed cell death modality, yet clinical translation is limited by insufficient spatiotemporal control and the risk of excessive inflammation. Photodynamically induced pyroptosis can address these constraints via precise, localized, and on-demand activation within tumors. Beyond local cytotoxicity, rapid membrane rupture accelerates exposure and release of tumor-associated antigens, danger-associated molecular patterns, and inflammatory mediators, reprogramming the tumor immune microenvironment toward an immunostimulatory state. This cascade promotes antigen-presenting cell recruitment and maturation, enhances antigen presentation, and strengthens T cell-driven systemic immunity, potentially extending therapeutic efficacy to nonirradiated tumors through a pyroptosis-associated abscopal effect. Herein, we present zwitterionic nanogels for the delivery of the FDA-approved photosensitizer verteporfin, leveraging its intrinsic fluorescence for imaging-guided irradiation and its mitochondrial localization for near-infrared-triggered photopyroptosis. The zwitterionic nanogels improve verteporfin solubility, pharmacokinetics, and tumor accumulation, and their intrinsic fluorescence supports real-time tumor visualization and irradiation guidance. Upon near-infrared activation, mitochondrial oxidative stress triggers gasdermin-mediated pyroptosis, inducing immunogenic cell death and activating systemic antitumor immune responses. In brief, this work presents a mitochondria-targeted zwitterionic nanoplatform that integrates imaging-guided photopyroptosis with systemic cancer immunotherapy for abscopal effect-enhanced tumor suppression.