NIR-Switched DNA Shutter Enables Reversible Intermittent cGAS-STING Activation for Enhanced Antitumor Immunity

With their remarkable activation efficiency, cGAS-STING agonists have emerged as a promising strategy to promote immunotherapy. However, continuous activation of the STING pathway may induce resistance and immune evasion, thus impairing the therapeutic effect. Considering repetitive transient rest could restore immune system function and avoid side effects, here we develop an intermittent STING agonist to reversibly activate the cGAS-STING pathway with "stimulation-suspension" patterns, which induce repetitive "activation-rest" intervals in immunotherapy with enhanced efficiency. Near infrared (NIR) switchable reversible DNA shutter (NIR-DNA shutter), as the intermittent STING agonist, is synthesized by conjugating a pair of segmented complementary DNA strands that incorporated Azobenzene (Azo) to the surface of upconversion nanoparticles (UCNPs). Low power 808 nm irradiation generates a high Vis/UV ratio for UCNPs upconversion emission, which induces <i>trans</i>-Azo isomerization and assembles dsDNA chain along UCNPs surface to activate STING pathway, while high power 808 nm irradiation generates a high UV/Vis ratio for UCNPs upconversion emission, which induces <i>cis</i>-Azo isomerization and disassembles dsDNA chain to pause STING pathway. Switching NIR irradiation powers reversibly converts the NIR-DNA shutter between "ON/OFF" statuses and programs the cGAS-STING pathway with repetitive "activation-rest" interval mode, which demonstrates superior therapeutic efficacy by remodeling the immune-environment and enhancing tumor cell killing compared with the constant STING agonist.