Researchers have achieved complete tumor elimination in mice with glioblastoma, the deadliest form of brain cancer, using a novel non-invasive treatment delivered through nasal nanodrops. The breakthrough, detailed this month in PNAS, leverages precisely engineered nanoscale structures to activate the immune system directly within the brain, overcoming a major hurdle in cancer immunotherapy.
Why Glioblastoma Remains Untreatable
Glioblastoma develops from star-shaped brain cells (astrocytes) and affects roughly three in 100,000 Americans. Its aggressive growth and resistance to conventional therapies make it almost always fatal. The primary challenge is delivering effective drugs across the blood-brain barrier, a protective shield that keeps most medications from reaching the tumor.
“We aimed to bypass this barrier and stimulate the immune system to fight glioblastoma without invasive procedures,” explained Dr. Alexander Stegh, a neurosurgery professor at Washington University in St. Louis. “Our research proves that precisely designed nanostructures can safely activate powerful immune pathways deep inside the brain.”
Reviving Immunity in “Cold” Tumors
Glioblastoma is considered an immune “cold” tumor, meaning it doesn’t trigger a natural immune response. Unlike “hot” tumors, which respond better to immunotherapy, glioblastoma evades detection. Scientists have sought to stimulate the STING pathway (stimulator of interferon genes), which activates immune defenses when foreign DNA is detected.
Previous STING-activating drugs degrade quickly and require direct tumor injection—a highly invasive method. Researchers sought a non-invasive solution.
“We wanted to spare patients unnecessary procedures,” said Dr. Akanksha Mahajan, a postdoctoral researcher. “We hypothesized that nanoscale platforms could deliver these drugs without surgery.”
Nanodrops: Gold Cores for Nose-to-Brain Delivery
The team collaborated with Dr. Chad Mirkin at Northwestern University, who developed spherical nucleic acids (SNAs)—nanoscale particles densely coated with DNA or RNA. SNAs are more effective at delivering drugs than traditional methods.
Researchers designed SNAs with gold nanoparticle cores and DNA fragments that activate the STING pathway in immune cells. The particles were administered via the nasal passages, exploiting the direct nerve connection to the brain.
This is the first time nanoscale therapy has triggered an immune response against brain tumors through intranasal delivery.
Tracking Nanodrops in Real Time
The researchers tagged the SNAs with a fluorescent marker detectable via near-infrared light. Administered to mice with glioblastoma, the particles traveled along the facial nerve pathway to the brain.
Once there, the immune response concentrated in tumor-adjacent immune cells. Activity was also detected in nearby lymph nodes, but the spread was limited, minimizing off-target effects. The STING pathway activated within immune cells, triggering a stronger anti-cancer attack.
Combining Therapies for Complete Elimination
When combined with medicines that activate T lymphocytes (another key immune cell), the two-dose nanotherapy eradicated tumors in mice and provided long-lasting immunity against recurrence. These results surpassed those of existing STING-targeting therapies.
Dr. Stegh emphasized that stimulating STING alone won’t cure glioblastoma, as the tumor employs multiple immune evasion tactics. His team is now developing nanostructures with multiple immune-activating features for broader therapeutic impact.
“This approach offers hope for safer, more effective treatments for glioblastoma and other cancers resistant to immunotherapy,” Dr. Stegh concluded. “It represents a crucial step toward clinical application.”
This research was funded by the National Cancer Institute and various philanthropic organizations. Disclosures include financial ties between researchers and companies developing SNA therapeutic platforms.
