A Nasal Route to the Brain: Nanotherapeutics Open a New Front Against Glioblastoma

Glioblastoma remains one of the most treatment-refractory malignancies in neuro-oncology, in large part because of its profoundly immunosuppressive microenvironment. These tumors are often described as “cold,” lacking the robust inflammatory signals that allow immunotherapies to engage. A growing body of research has focused on turning these tumors “hot” by activating innate immune pathways. Among the most extensively studied is the STING pathway, short for stimulator of interferon genes, a cytosolic DNA-sensing mechanism that triggers type I interferon responses and coordinates early antitumor immunity.

While synthetic STING agonists can prime a more active immune landscape within glioblastoma, their rapid degradation and poor tissue penetration have limited clinical progress. Most experimental designs have required direct intratumoral injections, which are invasive, not easily repeatable, and ill-suited for patients already burdened by neurological symptoms. Researchers at Washington University School of Medicine and Northwestern University have now advanced a novel strategy that addresses these challenges through the convergence of nanotechnology and intranasal drug delivery.

Reframing an Old Problem: How to Wake the Immune System Inside the Brain

GBM suppresses the innate immune system by down regulating pathways responsible for detecting danger signals. Among those pathways, the stimulator of interferon genes (STING) system plays a central role. STING functions as a cellular early-warning mechanism: when foreign DNA appears in the cytosol, STING triggers a cascade that produces type I interferons, potent signals that activate antigen presentation and T-cell priming.

Previous research has shown that activating STING inside GBM can increase immune infiltration and reduce tumor burden. However, available STING agonists degrade quickly in biological environments and require direct intratumoral injection for efficacy. Because sustained benefit requires repeated dosing, the clinical practicality is low; few patients can undergo repeated intracranial procedures without substantial risk.

The scientific challenge has therefore been clear: develop a delivery system that reliably activates STING inside the tumor without requiring a needle to enter the brain.

Spherical Nucleic Acids: A Nanostructure Designed for Cellular Entry

This is where the spherical nucleic acid platform becomes transformative. Invented by Northwestern University’s Chad A. Mirkin, PhD, SNAs consist of a nanoparticle core, often gold-densely wrapped with short DNA or RNA strands pointing outward like bristles. This geometry gives SNAs properties that linear nucleic acids lack:

• High stability against enzymatic degradation.

• Efficient cellular internalization.

• Controllable pharmacokinetics.

• The ability to act as potent immune stimulators.

In the present study, researchers engineered gold-core SNAs coated with DNA sequences known to activate the STING pathway. Their mission was to use the particle’s architecture to deliver these sequences into the precise immune cells embedded in or around GBM tumors.

A Noninvasive Delivery Route: From Nasal Cavity to Brain

One of the most distinctive features of this work is its mode of delivery. Rather than relying on systemic circulation, the team turned to a neural conduit that connects the nasal cavity directly to the brain: the olfactory–trigeminal pathway. Intranasal delivery to the CNS has long been studied conceptually, but nanoscale immunotherapies have not successfully engaged brain tumor immunity through this route, until now.

The researchers administered the STING-activating SNAs as droplets into the nasal passages of glioblastoma-bearing mice. Each construct carried a near-infrared tracer, enabling real-time tracking. Imaging revealed that the nanoparticles migrated along the trigeminal nerve into the brainstem and dispersed into the tumor region. Notably, they remained localized within the CNS, showing minimal distribution to peripheral tissues.

The confinement is clinically significant: it reduces the risk of systemic inflammation and concentrates immune activation at the tumor site.

Reprogramming the Tumor Microenvironment

Examination of brain tissue demonstrated robust activation of the STING pathway within tumor-associated immune cells. The effects included:

• Up regulation of interferon-stimulated genes.

• Increased presence and activation of antigen-presenting cells.

• Heightened inflammatory signaling in the tumor microenvironment.

• Immune activation extending to cervical lymph nodes.

These findings indicate that the therapy initiates both local and regional immune responses, an essential element of durable antitumor immunity.

The therapeutic effect became even more pronounced when paired with an agent that enhances T-cell activation. In this combined approach, one or two intranasal doses completely eradicated tumors in mouse models and generated long-term immune memory, preventing recurrence after re-challenge. Such durable responses are rarely seen in GBM preclinical studies.

Expanding Toward Multifunctional Immunotherapeutics

While these results are compelling, senior author Alexander Stegh, PhD, emphasizes an important constraint: STING activation alone cannot counteract the full suite of immunosuppressive mechanisms that operate in GBM. The tumor interferes with T-cell trafficking, suppresses antigen presentation, and produces cytokines that blunt immune activity.

The next phase of the work aims to integrate multiple immune stimulators into a single SNA construct, an approach made feasible by the modularity of nucleic acid chemistry. In principle, an SNA could be engineered to simultaneously activate STING, improve antigen presentation, enhance T-cell recruitment, and disrupt local immunosuppressive barriers. This would represent an entirely new class of CNS-directed combinatorial immunotherapy.

A New Paradigm for Noninvasive Brain Cancer Treatment

This study provides the first demonstration that nanoscale STING agonists can be delivered intranasally and still activate immune responses in glioblastoma. The implications extend beyond a single tumor type:

• Noninvasive, repeatable dosing becomes practical.

• Immune activation stays concentrated in the CNS, minimizing systemic toxicity.

• The platform can be engineered to carry multiple immune-modifying signals.

• The approach may apply to other immune-resistant brain tumors and metastases.

Intranasal nanomedicine, once considered scientifically speculative, now stands as a credible therapeutic strategy, one capable of bypassing the blood–brain barrier, engaging the brain’s immune circuitry, and potentially reshaping the trajectory of glioblastoma therapy.

As research progresses, this work marks a definitive shift: from forcing therapies into the brain to guiding highly engineered biological signals along the pathways the brain already uses.