Tetrahedral DNA Nanostructure with Interferon Stimulatory DNA Delivers Highly Potent Toxins and Activates the cGAS‐STING Pathway for Robust Chemotherapy and Immunotherapy

Abstract Tumor metastases and reoccurrences are considered the leading cause of cancer‐associated deaths. While highly efficient treatments for the eradication of primary tumors have been developed, the treatment of secondary or metastatic tumors remains poorly accessible. Over the past years, compounds that intervene through the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) signaling pathway against tumor metastases have emerged with potential for clinical development. While interferon stimulatory DNAs have demonstrated activation of this pathway, these compounds are associated with poor bioavailability, poor stability, and poor cancer selectivity, hindering their use for therapeutic applications. Herein, the encapsulation of a highly potent chemotherapeutic platinum(II) complex and the incorporation of interferon stimulatory DNA strands for activation of the cGAS‐STING pathway into multimodal tetrahedral DNA nanostructures (84bp‐TDN^ISD/56MESS) for combined chemotherapy and immunotherapy is reported. It is found that 84bp‐TDN^ISD/56MESS can work as not only a drug delivery carrier for highly potent toxins, but also an immunostimulant agent that can activate the STING pathway for antitumor immune responses. In a mouse breast cancer model, the DNA nanostructure is found to nearly fully eradicate primary as well as secondary/metastatic tumors, hence demonstrating its potential clinical translational value.