Super-resolution imaging of cGAMP-loaded mitochondria-targeting H-aggregation poly-photosensitizer vesicles for cancer photodynamic-immunotherapy

Authors

• Z Wang
• J Chen
• D Kiesewetter
• RD Leapman A Jin

Abstract

The activation of Stimulator of Interferon Genes (STING) through STING agonists has gained recognition as a robust and highly promising strategy in immunotherapy, with remaining challenges in the immunosuppressive tumor microenvironment and the safety concerns associated with the systemic administration of STING agonists. We have developed a poly-photosensitizer vesicle for encapsulated hydrophilic cGAMP to combine photodynamic therapy and STING activation to improve immunotherapeutic efficacy. The poly-photosensitizer vesicle employs three times higher singlet oxygen and superoxide yields than the small molecule photosensitizer under physiological conditions, owing to H-aggregation improves the energy matching between excited singlet and triplet states to promote the intersystem crossing (ISC) rate. We visualize the entire process of nanovesicles targeting mitochondria using super-resolution microscopy in vitro. Upon 671 nm laser irradiation in vivo, our collaborators have observed that hybrid type I and type II photodynamic therapy effectively kills primitive tumor cells and promote immunogenic cell death. Meanwhile, the cGAMP release activates cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This innate and adaptive immunity combination inhibited tumor growth in localized and metastatic murine cancer models. We are developing organ-on-chip models and super-resolution imaging methodologies to bridge these in vitro and in vivo results. Our findings demonstrate that targeted mitochondrial photodynamic therapy and local activation of STING results in systemic antitumor immunity and improve the therapeutic efficacy of checkpoint blockade.

Scientific Focus Area: Chemical Biology

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