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Scientists at the National University of Singapore presented their successful passage through the blood-brain barrier utilizing a modified strain of Lactobacillus plantarum. By administering an appetite-regulating hormone directly to the olfactory epithelium, the hormone reached its intended target.
Only the hormone molecules that were secreted traversed into the brain. The engineered Lactobacillus plantarum stayed within the nasal cavity, where it discharged its therapeutic payload, subsequently diffusing along the olfactory pathway into the brain.
Conventional techniques for addressing neurological disorders are significantly hindered by the highly protective characteristics of the blood-brain barrier. Intranasal treatments frequently experience swift clearance, resulting in a lack of sustained therapeutic release.
In the research article titled “Engineered Commensals for Targeted Nose-to-Brain Drug Delivery,” published in the journal Cell, the authors address these challenges by leveraging the inherent affinity of L. plantarum for the olfactory epithelium.
Lactobacillus plantarum was selected as the carrier organism due to its inherent ability to localize to the binding sites within the olfactory epithelium. Initially, L. plantarum was engineered to express and secrete hormones such brain-derived neurotrophic factor (BDNF), alpha-melanocyte-stimulating hormone, and leptin.
The experiments utilized in vitro models comprising nasal cell monolayers, as well as in vivo studies conducted with male mice aged between 6 to 8 weeks. Intranasal delivery of fluorescent-labeled bacteria enabled visualization of bacterial distribution.
As predicted, the genetically modified bacteria exhibited a specific localization within the olfactory epithelium and subsequently discharged their payloads into the neighboring cerebral regions. Mice fed a high-fat diet and administered hormone-secreting microbes demonstrated a reduction in body weight gain, decreased food intake, enhanced glucose tolerance, and a reduction in adipose tissue accumulation in comparison to control groups.
The findings further indicated that leptin secreted by the bacteria remained in the olfactory epithelium for a duration that exceeded that of recombinant leptin administered via intranasal delivery.
The results validate the method’s potential as a noninvasive transport for medicines aimed at the brain. Although the study employed an appetite-regulating hormone, this delivery system could be modified for the treatment of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and brain tumors, where the challenge of drug penetration into the brain persists as a significant obstacle.
Subsequent research endeavors will concentrate on the optimization of dosage and the evaluation of long-term safety associated with the method, thereby establishing a foundation for innovative therapies that have been seeking a secure means of crossing the blood-brain barrier.
Sources:
Haosheng Shen et al. (2025). Engineered commensals for targeted nose-to-brain drug delivery, Cell. DOI: 10.1016/j.cell.2025.01.017
https://phys.org/news/2025-02-bloodbrain-barrier-payload-bacteria.html
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