From Nose to Neurons: A Breakthrough Approach to Treating Brain Disorders

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Written by Nitin Sreekumar ‘25

Edited by Andrew Ni ‘26

What if the mysteries of the brain are not unlocked by invasive procedures, but something as mundane as taking a breath? From the familiar scent of morning coffee to the sharp smell of ammonia, our sense of smell does more than guide us through the world, it also may hold a direct connection to the brain. Recent discoveries suggest our noses may also serve as a direct gateway to the brain. The brain, often considered the body’s most vital organ, has a layer of protection called the blood-brain barrier (BBB), a  highly selective membrane that protects it from harmful substances carried in the blood. While this barrier is essential, it also prevents most drugs from reaching the brain, posing a significant challenge in developing effective therapeutics for brain disorders [2].

Recently, however, scientists have discovered a promising approach to get around the BBB using the nose. A study by Huang et al (2023) discovered that the olfactory epithelium (OE), a specialized region in the nose that picks up smells from the environment, can serve as a potential gateway to the brain. This is because nerves in the OE connect directly to the brain through the cranial bones, making it an ideal target for intranasal delivery of drugs. Intranasal drug delivery through the OE would enable non-invasive delivery of therapeutics directly to the brain while also improving effectiveness by avoiding breakdown by the liver and side effects in other areas of the body [3].

Despite the benefits, intranasal delivery has limitations. The OE has a small surface area which limits the amount of medication that can be delivered compared to traditional drug delivery methods like oral or injection. Furthermore, some of the medication can be lost in the process of absorption or degraded by enzymes in the OE. Finally, delivery can be inconvenient for patients as they may have to tilt their heads back or lie in unusual positions to help the medication travel through the nasal cavity [3].

To overcome these challenges, Dr. Matthew Chang and his team at the National University of Singapore, turned their attention to an unexpected ally, the bacteria that reside in the nose. The nose is known for its robust and diverse microbiome, and some of these bacteria have a direct connection to the brain by sharing metabolites. The researchers hypothesized that these bacteria could be used as carriers to transport therapeutics more efficiently [4].

They decided to use obesity as a model disease, given the brain's key role in regulating appetite. Using a strain of Lactobacillus, a common and safe probiotic bacteria, the scientists engineered it to carry and release appetite-regulating hormones directly to the OE. First, the researchers confirmed that Lactobacillus could bind to the OE by tagging it with FITC (fluorescein isothiocyanate), a fluorescent tracer dye. On administration it successfully released the tracer within the OE, where it eventually diffused into the olfactory bulb of the brain. With these positive results, the researchers then engineered the microbe to produce three appetite-regulating hormones. When obese mice received daily doses of these modified microbes they showed reduced food intake, leading to decreased weight gain and improved glucose and fat metabolism [4].

This research highlights the intricate relationship between the nasal microbiome and the brain, emphasizing how nasal bacteria can influence brain functions. Although these studies have only been conducted in animals so far, the findings suggest that in the future, modulating the olfactory microbiome could become a viable method for medical intervention. This technique holds significant potential for developing new treatments for a variety of brain-related diseases. By improving drug delivery to the brain, we could not only enhance therapeutic outcomes but also reduce side effects and the burden on patients in the future.  By turning a routine sniff into a precise method of drug delivery, we can reimagine how we treat brain-related conditions and improve countless lives.

References

1. Formica, M. L. et al. On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles. Applied Materials Today 29, 101631 (2022).

2. Alajangi, H. K. et al. Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders. Mol Brain 15, 49 (2022).

3. Huang, Q., Chen, X., Yu, S., Gong, G. & Shu, H. Research progress in brain-targeted nasal drug delivery. Front. Aging Neurosci. 15, 1341295 (2024).

4. Shen, H. et al. Engineered commensals for targeted nose-to-brain drug delivery. Cell S0092867425000467 (2025) doi:10.1016/j.cell.2025.01.017.