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

文章来源: 发布时间:2023-03-01

Lingpu Zhang#, Yuqi Wang#, Johannes Karges, Dongsheng Tang, Hanchen Zhang, Kexuan Zou, Jie Song, Haihua Xiao*

Adv. Mater. 2022, 35, 2210267


In recent years, DNA nanostructures have shown promising applications in biomedical fields such as detection, bioimaging, and targeted drug delivery. Due to their high stability, good biocompatibility and easy chemical modification, DNA tetrahedra (TDN) have been widely used to deliver chemotherapeutic drugs, nucleic acid drugs and loaded fluorescent probes to realize the integration of diagnosis and treatment of tumor therapy, etc., which have received high attention from scholars at home and abroad. However, the potential tumor immune activation effect of TDN has not been explored so far. Therefore, we designed a DNA tetrahedra (TDNISDs) formed by base complementary pairing of one interferon-stimulated DNA strand (ISD strand) and three single-stranded DNAs of specific sequences. Compared with ISD sequence-containing dimers and TDNs without ISD sequences, TDNISDs can dual activate the STING pathway through their physical topology and ISD sequences to selectively activate antigen-presenting cells and promote infiltration of tumor antigen-specific T cells and natural killer (NK) cells into tumors, exhibiting stronger immune activation effects. In addition, researchers were able to obtain TDNs containing ISD sequences of different lengths (42bp-TDNISD, 64bp-TDNISD and 84bp-TDNISD) by regulating the ISD chain length. Through further screening, the researchers found that 84bp-TDNISDhad a better immune activation effect. In addition, to further improve the therapeutic effect, the highly efficient platinum-based DNA embedding agent 56MESS could be introduced into 84bp-TDNISD, resulting in the nanodrug with DNA tetrahedra (84bp-TDNISD/56MESS). On the one hand, 84bp-TDNISD/56MESS can rapidly release 56MESS intracellularly, and the latter can activate the cGAS-STING pathway while rapidly killing cancer cells; on the other hand, 84bp-TDNISD itself can effectively activate the cGAS-STING pathway. In conclusion, 84bp-TDNISD/56MESS can not only deliver 56MESS for chemotherapy, but also activate the cGAS-STING pathway, induce anti-tumor immune response in mice, inhibit the growth of breast cancer, and prevent metastasis and recuhhence.