Biological Logic-Gated DNA Self-Assembly Strategy for Precision Tumor Imaging and Selective Activation of the cGAS-STING Pathway.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising target for cancer immunotherapy, but conventional synthetic nucleic acids often cause nonspecific activation and systemic inflammation, limiting clinical translation. To address this, we developed a programmable DNA nanosystem (MP-DNA) with AND-gate logic for tumor-restricted cGAS-STING activation. MP-DNA responds to two aberrant biomarkers in colon cancer: apurinic/apyrimidinic endonuclease 1 (APE1) and microRNA-10b. Upon simultaneous detection, MP-DNA triggers a hybridization chain reaction (HCR) to generate long double-stranded DNA polymers. These dsDNA products function dually as potent immunostimulants activating cGAS-STING and as in situ fluorescent reporters for real-time imaging. The localized immune activation enhances lymphocyte infiltration into the tumors. Additionally, MnO2 nanosponges (MnO2 NSs) are used as carriers that degrade in the tumor's reductive milieu, releasing Mn2+ to synergistically enhance STING activation. By employing endogenous tumor signals as logic inputs, this work presents an intelligent immunotherapy platform that integrates precise immune modulation with diagnostic feedback. Our study offers both a conceptual advance and a technological framework for designing programmable nucleic acid therapeutics that improve antitumor efficacy while minimizing off-target toxicity.