Photoactivated DNA Assembly and Disassembly for On‐Demand Activation and Termination of cGAS‐STING Signaling

Abstract Despite significant progress in DNA self‐assembly for interfacing with biology, spatiotemporally controlled regulation of biological process via in situ dynamic DNA assembly remains an outstanding challenge. Here, we report an optically triggered DNA assembly and disassembly strategy that enables on‐demand activation and termination of the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway. In the design, an activatable DNA hairpin is engineered with a photocleavable group at defined site to modulate its self‐assembly activity. Light activation induces the configurational switching and consequent self‐assembly of the DNA hairpins to form long linear double‐stranded structures, allowing to stimulate cGAS protein to synthesize 2′,3′‐cyclic‐GMP‐AMP (cGAMP) for STING stimulation. Furthermore, by endowing the pre‐assembled DNA scaffold with a built‐in photolysis feature, we demonstrate that the cGAS‐STING stimulation can be efficiently terminated through remote photo‐triggering, providing for the first time a route to control the temporal “dose” on‐demand for such a stimulation. We envision that this regulation strategy will benefit and inspire both fundamental research and therapeutic applications regarding the cGAS‐STING pathway.