DNA lesion-gated dumbbell nanodevices enable on-demand activation of the cGAS-STING pathway for enhancing cancer immunotherapy.

Utilizing the cGAS-STING pathway to combat immune evasion is one of the most promising strategies for enhancing cancer immunotherapy. However, current techniques for activating the cGAS-STING pathway often face a dilemma, mainly due to the balance between efficacy and safety. Here, we develop a uracil base lesion-gated dumbbell DNA nanodevice (UBLE) that allows on-demand activation and termination of the cGAS-STING pathway in tumor cells, thereby enhancing cancer immunotherapy. The UBLE integrates two deoxyuridines (dU) in the stem for DNA lesion recognition, two locked complementary primer sequences (primers A and B) for DNA self-assembly, and a Förster resonance energy transfer pair (Cy3 and Cy5) attached to the loop for activation assessment. Upon the orthogonal recognition of tumor-specific repair indicators (UDG and APE1), the UBLE undergoes a conformational change to create massive nicked double-stranded DNA (dsDNA) units. These units self-assemble to generate long fluorescent dsDNA structures, permitting selective evaluation and on-demand activation of the cGAS-STING pathway. Furthermore, we demonstrate that the UBLE can effectively activate the cGAS-STING pathway in tumor cells, enhancing NK cell-targeted cancer immunotherapy. This work develops a DNA lesion-gated strategy for on-demand activation and termination of the cGAS-STING pathway, affording an innovative avenue for enhancing cancer immunotherapy.