Advances in Nose-to-Brain Delivery for GBM and CNS Disorders

Executive Summary

Glioblastoma (GBM) and many central nervous system (CNS) disorders remain among the most challenging conditions to treat, largely due to the inability of many therapeutics to cross the blood–brain barrier (BBB). As a result, researchers and clinicians have increasingly turned their attention toward nose-to-brain delivery — an approach that uses the unique anatomy of the nasal cavity to bypass the BBB and deliver therapeutics directly to the brain.

This article provides a high-level overview of the evolving landscape of intranasal CNS delivery, focusing on why this route is attracting renewed interest for GBM and other neurological conditions, and highlighting its potential advantages.

The Challenge: Delivering Therapeutics to the Brain

The BBB protects the brain from harmful substances but also prevents many systemically administered therapies from reaching therapeutic concentrations in CNS tissue. For GBM and disorders such as Alzheimer’s, Parkinson’s disease, and neuroinflammation, this remains a major barrier to effective treatment (Pardridge, Drug Discovery Today, 2007).

Systemic administration often requires high doses to overcome this barrier, increasing the risk of toxicity while still achieving limited penetrance into the CNS.

These challenges have prompted increasing interest in alternative delivery routes that bypass the BBB entirely.

Why Nose-to-Brain Delivery Is Gaining Momentum

Intranasal delivery offers a unique opportunity to access the CNS by leveraging the anatomical features of the upper nasal cavity. Rather than relying on systemic circulation, certain molecules deposited in the nasal passages can be transported directly along neural pathways into the brain.

This concept has gained significant scientific attention due to several favorable properties:

1. Direct Access to the CNS via Established Anatomical Pathways

Two major pathways enable nose-to-brain transport:

• Olfactory pathway, located in the upper nasal cavity and directly connected to the olfactory bulb

• Trigeminal nerve pathway, which provides routes to deeper brain structures via branches that innervate the nasal mucosa

These pathways have been well described in preclinical and translational studies (Lochhead & Thorne, Advanced Drug Delivery Reviews, 2012).

2. Bypassing the Blood–Brain Barrier

Unlike systemic administration, intranasal delivery does not require a therapeutic to cross the BBB. This reduces reliance on chemical modifications, high dosing, or invasive procedures (Illum, Journal of Controlled Release, 2012).

3. Potential for Rapid CNS Exposure

Evidence suggests that nose-to-brain routes may allow for relatively fast distribution to key brain regions, an advantage in disorders where delayed penetration is a limitation (Thorne et al., PNAS, 2004).

4. Non-invasive and Patient-Friendly

Intranasal administration avoids surgical intervention and may fit well within outpatient or at-home care models. This is particularly relevant for chronic CNS diseases and for patients with impaired mobility.

Implications for GBM and CNS Disorders

While the exact therapeutic impact depends on the specific agent and disease context, the potential value of nose-to-brain delivery spans several areas.

1. Reaching Tumor Regions That Systemic Therapies Cannot

GBM tumors are embedded within complex neural architecture, where the BBB can remain partially intact — limiting the reach of many chemotherapeutics or biologics (Wen & Kesari, NEJM, 2008). Intranasal routes offer a conceptual strategy to bypass vascular limitations.

2. Enhancing Local Exposure While Reducing Systemic Burden

In CNS disorders with systemic side effects or dose limitations, a localized delivery route may allow for better CNS exposure without significant systemic escalation.

3. Broad Applicability Across Neurological Disorders

Research has explored intranasal approaches in conditions such as:

• Alzheimer’s disease

• Parkinson’s disease

• Traumatic brain injury

• Brain metastases

• Neuroinflammation

• Glioblastoma

(Palmisano et al., Pharmaceutics, 2019; Agrawal et al., CNS Drugs, 2018)

Although results vary, the breadth of interest reflects the conceptual advantages of non-invasive CNS targeting.

Barriers and Challenges — A Realistic View

Despite growing enthusiasm, nose-to-brain delivery still faces important challenges:

• Variability in nasal anatomy

• Mucociliary clearance that reduces residence time

• Limitations in how far and how consistently therapies can travel within neural pathways

• Need for reproducible, user-friendly delivery techniques(Chapman et al., Frontiers in Neuroscience, 2013)

These considerations reinforce that while the approach is promising, it remains an area of continued research rather than a uniform clinical solution.

Why Interest Is Increasing Now

Several broader shifts in medicine have accelerated interest in nose-to-brain pathways:

• Greater focus on precision CNS therapeutics

• The need for non-systemic options with improved tolerability

• Advances in device engineering that improve deposition in the upper nasal cavity

• A growing recognition that many CNS diseases are underserved by existing delivery routes

Collectively, these trends support the renewed attention on intranasal CNS delivery as a potential component of future multimodal care models.

The Path Forward

The next generation of nose-to-brain strategies is expected to emphasize:

• Non-invasive delivery

• Improved reproducibility of administration

• Compatibility with outpatient care

• Approaches that complement, rather than replace, existing therapies

• A careful balance of safety, tolerability, and patient convenience

These principles reflect the broader direction of CNS therapeutic innovation.

Conclusion

Nose-to-brain delivery represents a promising frontier for addressing some of the most persistent challenges in neuro oncology and CNS medicine. By bypassing the blood–brain barrier and leveraging direct anatomical pathways to the brain, intranasal strategies offer conceptual advantages for conditions like GBM and other CNS disorders where traditional systemic delivery falls short.

While significant scientific and clinical questions remain, the growing momentum behind this field reflects a shared goal across industry, clinicians, and researchers: finding more efficient, less burdensome, and better targeted ways to treat complex CNS diseases.

References

• Pardridge W., Drug Discovery Today, 2007

• Wen P., Kesari S., New England Journal of Medicine, 2008

• Thorne R. et al., PNAS, 2004

• Lochhead J., Thorne R., Advanced Drug Delivery Reviews, 2012

• Illum L., Journal of Controlled Release, 2012

• Chapman C. et al., Frontiers in Neuroscience, 2013

• Agrawal M. et al., CNS Drugs, 2018

• Palmisano A. et al., Pharmaceutics, 2019