Tetrahedral DNA nanostructures synergize with MnO to enhance antitumor immunity promoting STING activation and M1 polarization.

Stimulator of interferon genes (STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here, we showed that tetrahedral DNA nanostructures (TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn to enhance the expressions of IFN- and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn, we constructed a TDN-MnO complex and found that it displayed a much higher efficacy than TDN plus Mn to initiate macrophage activation and anti-tumor response both and . Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO. These findings provide new therapeutic opportunities for cancer therapy.