cGAS-agonistic Spherical Nucleic Acids reprogram the glioblastoma immune microenvironment and promote anti-tumor immunity

Intratumorally delivered STING-agonistic cyclic dinucleotides (CDN) exhibit therapeutic benefit in preclinical glioblastoma (GBM) models, but inadequate bioavailability limits CDN therapy to invasive intratumoral administration. Here, we have designed, synthesized, and developed a first-in-class cGAS- agonistic Spherical Nucleic Acid (SNA) structure that can reprogram the immunosuppressive GBM immune microenvironment by triggering cGAS-STING pathway activation. This strategy elicits potent anti-glioma activity when administered via non-invasive nose-to-brain delivery and overcomes immune checkpoint inhibitor (ICI) treatment resistance. The use of SNAs addresses the challenges of non-invasive nucleic acid delivery to intracranial tumor sites and establishes ISD45-SNAs as a novel immunotherapeutic modality for GBM treatment.