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

Tumor metastases and reoccurrences are considered the leading cause of cancer-associated deaths. While highly efficient treatments for the eradication of the primary tumor have been developed, the treatment of secondary or metastatic tumors remains poorly accessible. Over the last years, compounds that intervene through the immunogenic cGAS-STING signaling pathway against tumor metastases have emerged with potential for clinical development. While interferon stimulatory DNAs have demonstrated to activate this immunogenic pathway, these compounds are associated with poor bioavailability, poor stability, and poor cancer selectivity, rendering 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 could work as not only a drug delivery carrier for highly potent toxins but also an immunostimulant agent that can activate the STING pathway for anti-tumor immune responses. The nanomaterial demonstrated to nearly fully eradicate a primary as well as secondary/metastatic breast cancer tumor inside an animal model. This article is protected by copyright. All rights reserved.