Nose-to-Brain Drug Delivery via Intranasal Route: Nanocarrier-Based Strategies for Neurodegenerative and Central Nervous System Disorders

Abstract

Background: The treatment of central nervous system disorders is fundamentally constrained by the blood-brain barrier, a highly selective physiological interface that excludes more than 98% of small molecule drugs and virtually all macromolecular therapeutics from the brain parenchyma. The nose-to-brain delivery pathway, exploiting the unique anatomical continuity between the nasal mucosa and the central nervous system via the olfactory and trigeminal nerve networks, offers a non-invasive alternative route that allows drugs to bypass the blood-brain barrier and reach brain tissue directly. Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and epilepsy — for which current systemic pharmacotherapy is severely hampered by poor CNS penetration — represent particularly compelling targets for intranasal nose-to-brain drug delivery strategies.

Objective: This review critically examines the anatomical basis, transport mechanisms, nanocarrier platforms, formulation design considerations, characterization strategies, and therapeutic applications of nose-to-brain drug delivery for CNS disorders, with emphasis on advances reported in the published literature up to 2022.

Results and Discussion: Multiple nanocarrier platforms including mucoadhesive nanoparticles, lipid nanoparticles, solid lipid nanoparticles, nanoemulsions, cubosomes, and in situ gelling systems have been investigated for intranasal CNS delivery, collectively demonstrating substantially higher brain drug concentrations and improved pharmacodynamic outcomes in animal models compared to equivalent intravenous or oral doses. The olfactory epithelium and trigeminal nerve pathways are the principal routes of nose-to-brain transport, with transport efficiency critically dependent on particle size, surface charge, mucoadhesion, and formulation viscosity.

Conclusion: Nose-to-brain drug delivery via nanocarrier-loaded intranasal formulations represents a scientifically sound and pharmacologically promising approach to CNS drug delivery that addresses the fundamental limitation imposed by the blood-brain barrier. Translation to clinical practice requires resolution of key questions regarding human olfactory transport efficiency, dosing volume constraints, and nasal mucociliary clearance management.