Precision nose-to-brain therapeutics: Advances in drug delivery systems and emerging preclinical models

Intranasal administration has emerged as a promising non-invasive route for brain-targeted drug delivery, primarily due to its unique ability to bypass the blood-brain barrier (BBB) and facilitate direct brain targeting via neural pathways. Consequently, this route has been extensively investigated for treating diverse brain disorders, ranging from acute conditions to neurodegenerative diseases. Despite the advantages and clinical approval of several nasal products, the need for effective disease-modifying therapies (DMTs) of brain disorders remains unmet. Given that most brain disorders involve region-specific or cell-type-specific pathological changes, and that off-target effects may result in central nervous system toxicity, precision nose-to-brain delivery is critical. A major challenge to its clinical translation remains the lack of predictive, human-relevant preclinical models. Therefore, this review explores the challenges in nose-to-brain drug delivery development, highlights advanced intranasal delivery strategies for treating brain disorders, and discusses emerging in vitro models for evaluating nose-to-brain delivery efficiency. The work aims to promote the development and clinical translation of intranasal brain-targeted therapeutics.