Noninvasive Nasal Delivery of STING Agonists for Aggressive Brain Tumor Treatment

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Summary of  Proceedings of the National Academy of Sciences https://doi.org/10.1073/pnas.2409557122 
Dr. Akanksha S. Mahajan  et al.

Points

Researchers developed gold nanoparticle-based spherical nucleic acids to deliver immune-stimulating DNA oligonucleotides directly to the brain via intranasal administration.
The therapy targets the cGAS enzyme to trigger the STING pathway and produce endogenous cyclic dinucleotides that reverse tumor immunosuppression.
Intranasal delivery of these nanostructures in mouse models inhibited glioblastoma growth more effectively than traditional synthetic cyclic dinucleotides.
The treatment induces a proinflammatory microenvironment by increasing the presence of effector T cells and macrophages within the tumor.
Co-administration of this nanomedicine with immune checkpoint inhibitors abolished tumor development and resulted in long-term immunity against glioma.

Summary

This study investigated the efficacy of a novel intranasal nanomedicine, designated as ISD45-SNAs, for the treatment of glioblastoma (GBM) via activation of the cGAS-STING pathway. GBM typically presents as an immunologically “cold” tumor with a lymphocyte-depleted microenvironment, a challenge often compounded by the inability of therapeutics to cross the blood-brain barrier. To address this, researchers engineered spherical nucleic acids (SNAs) consisting of gold nanoparticle cores functionalized with interferon-stimulatory DNA oligonucleotides. These nanostructures bind directly to cGAS, catalyzing the production of endogenous cyclic dinucleotides (CDNs) to trigger a potent innate immune response superior to that of synthetic CDNs.

In syngeneic GBM mouse models, intranasal administration of ISD45-SNAs demonstrated significantly higher cellular accumulation and therapeutic potency compared to free CDNs. The treatment successfully inhibited tumor growth and prolonged survival by reversing the immunosuppressive phenotype of myeloid cells. Analysis of the tumor microenvironment revealed that ISD45-SNAs induced a proinflammatory state characterized by a marked enrichment of effector T cells and proinflammatory macrophages, effectively converting the cold tumor environment into a target for the immune system.

Furthermore, the study evaluated the synergistic potential of combining ISD45-SNAs with immune checkpoint inhibitors (ICI). When co-administered, this regimen abolished GBM tumor development and established long-term anti-glioma immunity in the animal subjects. These findings suggest that noninvasive nasal delivery of cGAS-activating SNAs represents a viable modality for overcoming bioavailability issues in neuro-oncology and significantly enhancing the efficacy of checkpoint blockade in aggressive brain malignancies.

Link to the article: https://www.pnas.org/doi/10.1073/pnas.2409557122#con1

References

Mahajan, A. S., Dussold, C., Kim, S., Jarvis, R., Hurley, L. A., Tommasini-Ghelfi, S., Park, J., Forsyth, C. M., Zhang, B., Miska, J., Heimberger, A. B., Mirkin, C. A., & Stegh, A. H. (2025). Cgas-agonistic spherical nucleic acids reprogram the glioblastoma immune microenvironment and promote antitumor immunity. Proceedings of the National Academy of Sciences, 122(45), e2409557122. https://doi.org/10.1073/pnas.2409557122