Second Near‐Infrared Phototheranostics with cGAS‐STING‐Activating Capacity for Photothermal Immunotherapy

Abstract Photothermal immunotherapy represents an effective approach for eliminating both local and metastatic tumors through priming of the tumor‐specific immune response. Cytosolic delivery of double‐stranded DNA via pH‐responsive vehicles is recently verified to activate the cyclic guanosine monophosphate–adenosine monophosphate (GMP‐AMP) synthase‐stimulator of interferon genes (cGAS‐STING) pathway, which is robust in activating both innate and adaptive antitumor immunity. Herein, multifunctional phototheranostics with excellent photothermal conversion capacity, second near‐infrared (NIR‐II) fluorescence, and cGAS‐STING activating capacity are prepared by encapsulating fish testis DNA and conjugated boron dipyrromethene tetramers with poly(lactic‐co‐glycolic acid) and poly(ethylene glycol)‐b‐poly(lactic‐co‐glycolic acid) via a CaCO 3 ‐assisted double emulsion method. The obtained phototheranostics (coined DB 4 CaP NPs) after intravenous administration gradually accumulate in tumor regions, as shown by NIR‐II fluorescence imaging. Together with local 915 nm laser exposure, primary tumors in mice treated with DB 4 CaP NPs could be effectively eradicated, with a complete response of 83.3%. Furthermore, such DB 4 CaP NPs could synergize with anti‐programmed cell death protein 1 immunotherapy to suppress the growth of distant unirradiated and rechallenged tumors through activating the antitumor immune response. This study highlights a promising strategy for eradicating tumors, particularly invisible and unresectable micronodules, through NIR‐II fluorescence imaging‐guided photothermal immunotherapy.