Challenges and strategies for nose-to-brain delivery in treating neurological disorders

The nose-to-brain route is a promising noninvasive strategy to circumvent the blood-brain barrier (BBB) and directly target the central nervous system (CNS), addressing the pivotal challenge of poor drug delivery in neurology. This review provides a strategic overview of the biological barriers and advanced nano-strategies, offering a roadmap for future research and clinical translation.

This review explores the nose-to-brain route, from its anatomical basis and physiological barriers (mucus, epithelium, brain distribution), to interventional nanocarriers. These include systems with mucoadhesive/penetrative coatings, junction modulators, and targeted, environmentally responsive designs. The literature search was conducted utilizing databases such as PubMed and Web of Science, covering records from their inception up to August 2025, using a combination of keywords and MeSH terms including 'nose-to-brain delivery,' 'intranasal administration,' 'nanoparticles,' and 'neurological disorders.'

Despite the remarkable preclinical progress in enhancing brain drug concentrations, the clinical translation of nose-to-brain nanoplatforms remains hindered by challenges related to long-term safety, inter-individual variability, and scalable manufacturing; future success hinges on the development of intelligent, responsive systems and interdisciplinary collaboration to achieve personalized and effective neurological therapies.