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Crossing the blood–brain barrier with a payload via engineered bacteria

Researchers at the National University of Singapore have reported crossing the blood–brain barrier with help from a modified Lactobacillus plantarum. By delivering an appetite-regulating hormone directly to the olfactory epithelium, the hormone was able to reach its target.

Only the secreted hormone molecules crossed into the brain. Engineered Lactobacillus plantarum remained in the nasal passage, where it released its therapeutic payload, which then diffused along the olfactory pathway into the brain.

Current approaches to treating neurological conditions suffer from the highly protective nature of the blood–brain barrier. Intranasal therapies often encounter rapid clearance without a sustained therapeutic delivery.

In the study "Engineered Commensals for Targeted Nose-to-Brain Drug Delivery," in Cell, researchers address these challenges by exploiting L. plantarum's natural affinity for the olfactory epithelium.

L. plantarum was chosen as a delivery vector as it naturally localizes to the olfactory epithelium binding sites. Initial investigations involved engineering L. plantarum to express and secrete hormones such as leptin, alpha-melanocyte-stimulating hormone and brain-derived neurotrophic factor (BDNF).

Experiments incorporated in vitro models using nasal cell monolayers and in vivo studies with male mice aged 6 to 8 weeks. Intranasal administration of fluorescent-labeled bacteria allowed visualization of bacterial localization.

As expected, the engineered bacteria localized specifically in the olfactory epithelium and released their payloads into adjacent brain regions. Mice fed a high-fat diet and treated with hormone-secreting bacteria exhibited reduced body weight gain, lower food consumption, improved glucose tolerance and diminished adipose tissue deposition compared with control groups.

Findings further indicated that leptin secreted by the bacteria persisted in the olfactory epithelium longer than recombinant leptin delivered intranasally.

Results support the method's potential as a noninvasive vector for brain-targeted therapies. While the study used an appetite-regulating hormone, this delivery system could be adapted for neurological conditions such as Parkinson's disease, Alzheimer's, and brain cancers, where drug penetration into the brain remains a major hurdle.

Future studies will also focus on dosage optimization and long-term safety assessments of the method, laying the groundwork for novel treatments that have been waiting for a way to safely cross the blood–brain barrier.