Nose-to-Brain Delivery

Nose-to-brain delivery exploits the only place where the central nervous system comes close to the outside world. The olfactory epithelium at the roof of the nasal cavity is penetrated by olfactory receptor neurons whose axons pass through the cribriform plate into the olfactory bulb, and the trigeminal nerve supplies the respiratory epithelium with branches reaching the brainstem. Molecules are thought to travel in the perineural and perivascular spaces surrounding these fibres, reaching cerebrospinal fluid and brain within minutes without ever crossing the blood-brain barrier.

The anatomy scales badly. Olfactory epithelium occupies a large share of the rodent nasal cavity but only a small patch at the roof of the human one, so the fraction of an administered dose that reaches the relevant surface is far smaller in people. Deposition is governed by device and spray geometry, the deliverable volume per nostril is small, and mucociliary clearance sweeps material toward the pharynx within roughly fifteen to twenty minutes. Intranasal insulin, the most studied case, has produced encouraging small studies and a large multi-site Alzheimer's trial that did not show a cognitive benefit, with device performance a confounder. Intranasal oxytocin studies find only small and inconsistent rises in cerebrospinal fluid.

The useful conclusion is that the nasal route is real but low-capacity, and it competes with ordinary systemic absorption across the same mucosa. Approved intranasal drugs acting on the brain, such as esketamine and naloxone, work by absorption into blood rather than by direct nerve transport.

The error is detection presented as delivery. Finding a labelled peptide in brain tissue after nasal dosing shows transport occurred; it does not show the concentration reached anything near a receptor-occupying level, and rodent-derived fractions do not transfer to humans.