Antiglioma Activity of Bimodal cGAS-Agonistic  and STAT3-Inhibitiory Spherical Nucleic Acids

Mahajan, Akanksha Sanjay

doi:https://doi.org/10.21985/n2-btf6-4t42

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Antiglioma Activity of Bimodal cGAS-Agonistic and STAT3-Inhibitiory Spherical Nucleic Acids

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Stimulation of the cGAS-STING (cycle GMP-AMP synthase-Stimulator of Interferon Genes) pathway increases T cell activation and tracking into the tumor and reverses the immunosuppressive phenotype of myeloid cells. Direct targeting of the STING receptor using synthetic cyclic dinucleotide (CDN) ligands represents an attractive immunotherapeutic strategy for the treatment of lymphocyte-depleted and myeloid cell-enriched tumors, such as Glioblastoma (GBM). This approach, however, is limited by the metabolic instability of CDNs, and the presence of immune evasive and STING-inhibitory mechanisms in the tumor microenvironment (TME), including and especially those orchestrated by the master transcriptional regulator of inflammation and immunity STAT3 (Signal Transducer and Activator of Transcription 3). To activate cGAS anti-tumor responses and concomitantly inhibit STAT3-driven immunosuppression in the GBM TME, we generated Spherical Nucleic Acids (SNAs) that consist of a nanoparticle core densely functionalized with a shell of radially oriented stem-loop DNA oligonucleotides containing a guanine repeat element flanked by palindromic STAT3 decoy sequences. Bimodal SNA architectures, via multivalent and high-affinity binding of cGAS and STAT3 proteins, induced type I interferon (IFN) and proinflammatory cytokines more potently than free oligonucleotide or clinically tested CDNs; recruited and activated T and natural killer cells; reprogrammed immunosuppressive tumor-associated macrophages (TAMs); prevented STAT3 nuclear translocation and transactivation; reduced tumor cell viability; and elicited strong anti-tumor activity, with complete and lasting regression of immune checkpoint-resistant orthotopic GBM tumors. Our study established multifunctional SNAs as a first-in-class, single-entity nucleic acid therapeutic for targeting multiple immune pathways in GBM.

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