The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood–brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine5-enkephalin, encapsulated within chitosan amphiphile nanoparticles. Via the oral route the nanoparticle–prodrug formulation increased the brain drug levels by 67% and significantly increased leucine5-enkephalin’s antinociceptive activity. The nanoparticles facilitate oral absorption and the prodrug prevents plasma degradation, enabling brain delivery. Via the intravenous route, the nanoparticle–prodrug increases the peptide brain levels by 50% and confers antinociceptive activity on leucine5-enkephalin. The nanoparticle–prodrug enables brain delivery by stabilizing the peptide in the plasma although the chitosan amphiphile particles are not transported across the blood–brain barrier per se, and are excreted in the urine.