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‐TDNISD/56MESS) for combined chemotherapy and immunotherapy is reported. It is found that 84bp‐TDNISD/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.

Polyphotosensitizer‐Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy

“…To further investigate the effect of NP2+L on the release of DMAPs and DC maturation, BMDCs were extracted from mice, which were then co‐incubated with pretreated C4‐2 cells according to the previous report. [ 26 ] Subsequently, the DCs were examined and analyzed using flow cytometry. The results shown in Figure 5F,G demonstrated the highest percentage of DC maturation (CD80 + CD86 + ) was up to 40.5% caused by coincubation of BMDC with NP2+L‐pretreated tumor cells, which was 1.38 times higher than that caused by coincubation with NP2‐ pretreated tumor cells.…”

Functional Nucleic Acid-Based Immunomodulation for T Cell-Mediated Cancer Therapy

“…In addition, this tetrahedron loaded with anticancer drug 56MESS was constructed to improve the efficacy of cancer treatment (Figure 3c). 100 Although cGAS-STING-mediated DNA sensing played an important role in mediating antitumor immunity, its working mechanism in T cells remained unclear. Based on this, Li et al studied the mechanism of how the cGAS-STING pathway maintained the stemness of CD8 + T cells and explored its potential in antitumor T cell therapy.…”

Disulfide-containing polymer delivery of C527 and a Platinum(IV) prodrug selectively inhibited protein ubiquitination and tumor growth on cisplatin resistant and patient-derived liver cancer models

“…Platinum anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, are the first-line anticancer alkylating agents in clinic practice [ 20 , 21 ]. These drugs can cause DNA damage and induce cell apoptosis by cross-linking with DNAs in cancer cells [ 22 , 23 ]. Unfortunately, the DNA repair machinary is powerful in cancer cells, resulting in resistance to platinum drugs [ 24 , 25 ].…”