Direct cGAMP Delivery via Iron Oxide Nanoparticles for Enhanced STING Activation and Durable Antitumor Immunity

Activation of the stimulator of interferon genes (STING) pathway holds immense potential for cancer immunotherapy. However, clinical translation of STING agonists such as cyclic GMP-AMP (cGAMP) is hindered by their inherent instability and poor cellular uptake efficacy. Herein, we report an iron oxide nanoparticle (IONP)-based carrier for delivering cGAMP via coordination chemistry. The ribose, phosphate, and adenine on cGAMP were leveraged to directly bind IONP, resulting in cGAMP-functionalized IONPs (Fe-cGAMP). Such a design greatly improved the cellular uptake and STING activation efficacy of cGAMP. Beyond delivery, IONPs promoted reactive oxygen species (ROS) production and activated Toll-like receptors, leading to synergistic immune activation alongside cGAMP. Fe-cGAMP exhibited robust antitumor effects in multiple mouse tumor models. In combination with immune checkpoint inhibitors, Fe-cGAMP could induce complete tumor remission in over 50% of treated mice, and these mice also remain tumor-free upon a subsequent challenge, demonstrating strong and long-lasting antitumor immune responses.