Glioblastoma is one of the most aggressive and fatal brain cancers, progressing rapidly and leaving patients with very limited treatment options. A major challenge has been delivering effective therapies to the brain without invasive procedures, as most drugs struggle to cross protective biological barriers. Researchers now report a noninvasive strategy that delivers potent immune-activating therapy to the brain through the nose, triggering strong anti-tumor responses and eliminating tumors in animal models.

In the research led by Washington University School of Medicine in St. Louis (St. Louis, MO, USA), in collaboration with Northwestern University (Evanston, IL, USA), the investigators focused on using precisely engineered nanostructures assembled from nanoscale materials to transport immune-stimulating drugs into the brain. The approach is based on spherical nucleic acids, nanostructures built around a nanoparticle core and densely coated with short strands of DNA. These structures are designed to activate the STING pathway, a key immune signaling mechanism that helps cells detect threats and initiate immune defense, but without requiring direct injection into brain tumors.

To avoid invasive brain surgery, the researchers delivered the nanomedicine intranasally as small droplets. After administration through the nasal passages, the nanostructures traveled along nerve pathways connecting the face to the brain, allowing them to bypass the blood–brain barrier and reach tumor sites directly. Once inside the brain, the nanostructures selectively entered immune cells within and around glioblastoma tumors. Importantly, the therapy remained localized to the brain, minimizing spread to other organs where immune activation could cause harmful side effects.

The therapy was tested in mouse models of glioblastoma, where imaging confirmed successful delivery of the nanomedicine to brain tumors. Analysis of immune cells showed robust activation of the STING pathway specifically within the tumor environment, effectively “warming up” glioblastoma tumors that normally evade immune detection. When combined with drugs that enhance T-cell activity, the treatment eliminated tumors with just one or two doses and generated long-lasting immune memory that protected against tumor recurrence. The outcomes surpassed those of existing STING-based therapies that rely on direct tumor injection.

The study, published in Proceedings of the National Academy of Sciences, demonstrates that intranasal delivery of immune-activating nanomedicine can safely and effectively stimulate anti-tumor immunity in the brain. This strategy could reduce the need for repeated invasive procedures while improving treatment effectiveness for glioblastoma, a cancer that has long resisted immunotherapy. Researchers are now working to expand the platform by incorporating additional immune-activating components into the nanostructures. The goal is to target multiple immune pathways simultaneously, potentially extending the approach to other immune-resistant cancers and moving closer to clinical testing.

“With this research, we’ve shown that precisely engineered nanostructures, called spherical nucleic acids, can safely and effectively activate powerful immune pathways within the brain. This redefines how cancer immunotherapy can be achieved in otherwise difficult-to-access tumors,” said Alexander H. Stegh, PhD, co-corresponding author of the study. “This is an approach that offers hope for safer, more effective treatments for glioblastoma and potentially other immune treatment-resistant cancers, and it marks a critical step toward clinical application.”

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