J-Aggregated indocyanine green-loaded exosomes enable photoactivatable cytoplasmic delivery of STING agonist for targeted pancreatic cancer immunotherapy

Intracellular delivery of stimulator of interferon genes (STING) agonist is crucial for targeted cancer therapy while minimizing off-target cytokine storms. In this study, we engineer tumor cell-derived exosomes as homotypic nanocarriers for the intracellular delivery of STING agonist, enabling tumor-specific STING activation to enhance photoimmunotherapy against pancreatic cancer without systemic toxicity. To enable photo-controlled spatiotemporal release of the STING agonist, we encapsulate FDA-approved photosensitizer indocyanine green in the confined exosomal membranes, facilitating J-aggregate formation to enhance the singlet oxygen generation via increased intersystem crossing. Near-infrared light irradiation triggers rupture of both exosomal and lysosomal membranes, resulting in photoactivatable burst release and cytoplasmic trafficking of STING agonist SR-717, which elicits the tumor-specific STING activation in pancreatic cancers. Such STING activation induces robust immune responses with elevated immunogenicity and antigenicity, and totally suppresses off-target toxicity. This approach demonstrates potent therapeutic efficacy in murine pancreatic tumor models, leading to long-term immunological memory. Our findings offer a novel strategy for STING agonist delivery, improving the safety and efficacy of photoactivatable immunotherapy for difficult-to-treat cancers.