Assembled DNA Nanostructure to Precisely Induced cGAS‐STING Activation for Cancer Immunotherapy

Triple-negative breast cancer (TNBC) has emerged as a major challenge in cancer therapy due to its aggressive nature and lack of effective targeted treatments. Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to stimulate innate immunity is considered a promising strategy for TNBC treatment. However, current STING agonists are limited by several severe drawbacks that hinder their further application. Herein, a cross-shaped DNA skeleton was rationally engineered by leveraging programmable DNA assembly and AS1411 aptamer-mediated tumor targeting to achieve specific activation of the cGAS-STING pathway. The DNA nanoarchitecture exhibited outstanding resistance to nuclease-mediated degradation and achieved nucleolin-targeted cellular internalization, thereby facilitating efficient activation of the cGAS-STING signaling cascade and eliciting potent innate immune responses. In vitro and in vivo evaluations further validated that the DNA scaffold not only triggered innate immune activation but also inhibited tumor progression in TNBC models. Overall, this work provides a promising strategy for the development of safe and effective TNBC immunotherapy.