Self-assembling modified neuropeptide S enhances nose-to-brain penetration and exerts a prolonged anxiolytic-like effect

Anxiety disorders are the most common mental diseases and can greatly disrupt everyday life. Although there has been substantial research on anxiety disorders, novel therapeutics are needed. Neuropeptide S (NPS) is a potential therapeutic candidate owing to its strong anxiolytic activity; however, some disadvantages, such as its poor metabolic stability and inability to cross the blood–brain barrier (BBB), limit its use in the clinic. Herein, inspired by nose-to-brain drug delivery strategies, an endogenous 20-amino-acid-long mNPS peptide was modified by incorporating palmitic acid into its functional Lys12 side chain (M-3), which was expected to facilitate nose-to-brain penetration and exert a prolonged anxiolytic-like effect compared to mNPS. We found that M-3 assembled into nanofibers that retained the bioactivity of NPS and exhibited obvious improvements in metabolic stability. Notably, as expected, self-assembled M-3 was able to penetrate into the brain and exert anxiolytic effects. The elevated plus-maze (EPM) results further revealed that M-3 could produce prolonged anxiolytic-like effects in mice. In vivo imaging studies revealed that self-assembled M-3 could be efficiently transported from the nasal cavity to the brain. Furthermore, when intranasally administered, this molecule exhibited a significantly prolonged anxiolytic-like effect, which further illustrated that this molecule has a potent nose-to-brain penetration in vivo. Overall, this self-assembled nanofiber showed potent nose-to-brain penetration ability and prolonged bioactivity.