Engineered commensals for targeted nose-to-brain drug delivery

Intranasal administration through the olfactory epithelium (OE) presents a direct pathway for brain-targeted therapeutic delivery, although its feasibility is hampered by the anatomical and absorptive limitations of the OE. In this study, we identified Lactobacillus plantarum WCFS1 (Lp), a commensal strain with a natural affinity for the OE and engineered it to function as a vector for cerebral drug delivery. Upon intranasal administration, Lp released specific payload molecules within the OE, with subsequent transport and accumulation in the brain. The therapeutic efficacy of Lp was further validated by the recombinant production and secretion of appetite-regulating hormones. When administered intranasally in a murine model of obesity prevention, the engineered Lp significantly alleviated obesity-related symptoms. This was evidenced by decreased appetite, reduced body weight gain, and improved glucose metabolism and fat mass deposition. Our study demonstrates the capability of Lp as an intranasal delivery vehicle, emphasizing its potential for brain-targeted therapeutic applications. [Display omitted] •Intranasal Lactobacillus plantarum (Lp) targets the mouse olfactory epithelium (OE)•Intranasal Lp releases payloads in the OE, facilitating transport to the brain•Intranasal Lp-secreted appetite-regulating hormones reduce obesity in mice•Lp-secreted Leptin shows sustained effects over pure Leptin when delivered intranasally Shen et al. investigate the use of Lactobacillus plantarum, a commensal bacterial strain, as a chassis for targeting the olfactory mucosa to facilitate precise nose-to-brain delivery of therapeutic molecules. When engineered to secrete appetite-regulating hormones, intranasal delivery of L. plantarum alleviates obesity-related symptoms in a mouse model.