Summary

Getting therapeutic drugs into the brain is a huge problem. Most drugs cannot get into the brain, making it incredibly difficult to develop therapies for major brain disorders, such as epilepsy, stroke, brain cancer, and neurodegenerative diseases. The problem is with the blood-brain barrier which is designed to allow entry of nutrients but not most other substances. Multiple research facilities in Singapore and China teamed up to develop a novel system evaluated in mice to overcome this problem. Proof of concept demonstrated Intranasal delivery of macromolecular hormones induced weight loss in mice. Results were recently published in the prestigious journal Cell in 2025 (1).

Blood Brain Barrier: What is it? How does it block drug delivery?

  • The blood-brain barrier (BBB) is a highly selective semipermeable border that regulates the transfer of substances between the circulatory system and the central nervous system (CNS) (2).
  • The BBB allows passage of small, lipid-soluble molecules with a molecular weight less than 400 Da (e.g. oxygen, carbon dioxide, and some hormones). and small non-polar molecules. It also actively transports essential nutrients like glucose and amino acids using specific transport proteins.
  • The structure of the BBB is primarily due to endothelial cells that line the interior of blood vessels in the brain. These cells create a nearly impermeable seal. The endothelial cells have specific surface receptors to transport certain proteins which facilitate the selective movement of essential substances across the barrier (3).
  • The BBB poses challenges for drug delivery to the brain. More than 98% of small-molecule drugs and all macromolecular therapeutics are prevented from entering the brain (3). This limitation has led to ongoing research in developing strategies to enhance drug delivery across the BBB for treating various neurological disorders and brain cancers (2).

The Solution: Nose to brain drug delivery using olfactory-epithelium (OE)-binding nasal commensal probiotic bacterium

The science behind nose-to-brain drug delivery

  • The nose-to-brain connection is a direct pathway that allows substances to travel from the nasal cavity to the brain, bypassing the blood-brain barrier. This connection is facilitated by the olfactory region in the upper part of the nasal cavity, which is directly linked to the brain’s frontal cortex and olfactory bulb (OB) via olfactory nerves (3,4).
  • Biological molecules in the OB progress through the nose layers to the brain through various pathways These include intranasal drug delivery for various small therapeutic agents like insulin, piperine, quercetin, curcumin, nerve growth factor essential fibroblast growth factor, oxytocin, melatonin, vitamin B-12 (5,6).

Technological breakthrough by Shen et al (1)

The authors engineered Lactobacillus plantarum (Lp) to function as a vector for cerebral drug delivery. Lactobacillus plantarum is a probiotic bacterium that is found in fermented foods and the human gastrointestinal tract. It has an affinity for the olfactory epithelium (7).

  • Eight probiotic bacterial strains were tested for binding to n-acetyl heparin sulfate (NaHS) found exclusively on the olfactory epithelium. Lactobacillus plantarum was the strongest binder, positioning it as a potential candidate for drug delivery.
  • Proof of concept was provided by labeling the bacteria with a fluorescent moiety and showing preferential accumulation in the lamina propria region under the epithelium, and then transmission to the olfactory bulb (OB) in the brain and finally to broader regions of the brain.

In vivo proof of concept, induction of weight loss

  • Lactobacillus plantarum were separately engineered to express and secrete three appetite regulating hormones, Leptin, a-Melanocyte Stimulating Hormone (MSH), and Brain Derived Neurotrophic Factor (BDNF).
  • Administration of high doses of wild type Lp caused nasal polyps and reduced consumption and rapid weight loss. Moderate doses did not have these effects.
  • Administrating moderate doses of the engineered Lp to mice on a high-fat diet showed reduced weight gain at 3 weeks for leptin and at 4 to 5 weeks for MSH and BDNF.
  • Significant reduction in food uptake was seen in the groups of mice with leptin and MSH dosing.
  • The engineered microbes also enhanced glucose metabolism as evidenced by significantly lower fasting glucose levels.
  • To demonstrate effectiveness in preventing obesity in lean mice, an eight-week intranasal treatment of leptin Lp to mice showed reduced accumulation of peripheral adipose tissue (subcutaneous, peri-gonad, and peri-renal).

Consequences of Nose to Brain delivery success

Nose-to-brain delivery systems offer several advantages that could enhance treatment outcomes. Through bypassing the BBB, this method allows drugs to directly access the CNS, overcoming a major obstacle in treating neurological disorders (8,9). The method allows for higher bioavailability by avoiding first-pass metabolism in the liver and systemic circulation, a larger proportion of the drug can reach the brain, potentially increasing therapeutic efficacy (9). It has a rapid onset of action: The direct route to the CNS enables faster drug absorption and quicker therapeutic effects, which is crucial for treating acute neurological conditions (8).

References

  1. Shen et al. Engineered commensals for targeted nose-to-brain drug delivery. Cell 2025 https://doi.org/10.1016/j.cell.2025.01.017
  2. Wu et al. The blood-brain barrier: Structure, regulation and drug delivery. Nature, Signal Transduction and Targeted Therapy 8:217, 2023.
  3. Alexander and Saraf. Nose-to-brain approach: a key to easily accessing the brain for the treatment of Alzheimer’s disease. Neural Regen Res. 13:2102,2018.
  4. Mehta et al. The brain-nose interface: A potential cerebrospinal fluid clearance site in humans. Front. Physiol. 12:01, 2022.
  5. Ganger et al. Tailoring formulations for intranasal nose-to-brain delivery. Pharmaceutics 10:116,2018.
  6. Huang et al. Research progress in brain-targeted nasal drug delivery. Aging Neurosci 15:1, 2024.
  7. Asaru et al. In vitro importance of probiotic Lactobacillus plantarum related to medical field. Saudi J Biol Sci. 23:S6, 2015.
  8. Ghandi et al. Nasal delivery to the brain: Harnessing nanoparticles for effective drug transport. Pharmaceutics 16:481,2024.
  9. Ruigrok and de Lange. Emerging insights for translational pharmacokinetic and pharmacokinetic-pharmacodynamic studies: towards prediction of nose-to-brain transport in humans. AAPS J 17:492,2015.

 

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