Scientists at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have developed a ground-breaking technique to deliver therapeutic molecules directly to the brain, bypassing the blood-brain barrier.
Led by Dr Haosheng Shen, lead researcher from the Synthetic Biology Translational Research Programme, NUS Medicine and the NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI) this novel approach utilises a naturally occurring nasal bacterium, Lactobacillus plantarum (Lp), which was genetically engineered to produce therapeutic compounds and release them through a specific nose-to-brain pathway. Their research was published in leading life sciences journal, Cell.
The blood-brain barrier (BBB) plays a crucial role in protecting the brain from harmful substances but also poses significant challenges to delivering medications for neurological conditions. Existing drug delivery methods often struggle with limited efficiency and require invasive procedures. To address these challenges, the team identified a strain of Lp with a natural affinity for the olfactory mucosa, a specialised tissue located in the upper part of the nasal cavity responsible for the sense of smell. This tissue also provides a direct pathway to the central nervous system, enabling targeted intranasal drug delivery.
Engineered to bind
However, intranasal drug delivery to the brain is hindered by the small surface area of the olfactory mucosa and the rapid clearance of drugs by the body. To work around this, the team engineered that strain of Lp to bind to N-acetyl heparan sulfate (NaHS, a long chain of sugar molecules that plays important roles in cell signalling, structural support, and protein interaction) in the olfactory epithelium. This binding enables the localised and sustained release of medication, which minimises systemic absorption and enhances bioavailability in the brain.
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The engineered Lp strain was able to produce appetite-regulating hormones, which the team used to demonstrate potential in treating brain-related disorders. In preclinical studies, intranasal administration of the modified bacteria resulted in reduced appetite, lower body weight gain, improved glucose metabolism, and decreased fat accumulation. The medication, after being released at the olfactory mucosa, successfully reached and accumulated in the brain.
Neurological conditions
By bypassing the BBB, this approach offers a more efficient way to deliver treatments for neurological conditions, including neurodegenerative diseases and conditions requiring peptides or proteins that typically do not cross the BBB. This targeted delivery method leverages the unique anatomical and biological properties of the olfactory mucosa, overcoming key barriers that have historically limited the effectiveness of brain-targeted therapies.
“This study illustrates the potential of engineered bacteria to serve as precise delivery vehicles for brain-targeted therapies,” said Dr Shen. “Our findings could pave the way for novel treatments of neurological diseases, leveraging the underexplored connection between nasal microbiota and brain function.”
Human trials
According to Dr Shen, the next phase of research will focus on optimising dosing regimens and conducting human clinical trials to confirm the efficacy and safety of the approach. Researchers will also investigate additional therapeutic applications, particularly in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s.
Professor Matthew Chang, Director of the Synthetic Biology Translational Research Programme, NUS Medicine and SynCTI, added, “Our research highlights the potential of nasal bacteria as non-invasive vehicles for brain drug delivery, and also underscores the importance of further exploring the relationship between the olfactory microbiome and brain health. By utilising bacteria with natural affinities for key areas in the nasal cavity, we may unlock new strategies for managing neurological disorders.”
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