MicroRNA‐Responsive DNA Dendrimer Acts as a Smart STING Signal Amplifier

Abstract The cGAS‐STING (cyclic GMP‐AMP synthase/stimulator of interferon genes) pathway is emerging as a promising target for cancer immunotherapy. However, developing specific and effective strategies for activating the cGAS‐STING pathway in tumors is still challenging. Here, a microRNA‐21 (miR‐21)‐responsive nucleic acid system, as a STING signal amplifier, is designed based on the branched catalytic hairpin assembly (bCHA). The effects of three types of dsDNA structures (linear dsDNA, Y scaffold dsDNA, and dsDNA dendrimer) on cGAS‐STING activation are systematically studied. This study demonstrates that dsDNA dendrimer can induce the most effective liquid–liquid phase separation in a miR‐21‐dependent manner, allowing the controllable activation of cGAS‐STING in both cancer cells and dendritic cells. Given the programmable nature of nucleic acid structure, this study will enable a readily accessible platform for integrating with immunotherapeutic strategies while opening new avenues for controllable, tumor‐specific activation of STING agonists.