Differential targeting of olfactory epithelium and respiratory epithelium in nose-to-brain drug delivery
Anisha D’Souza, Valentina DiFrancesco, Alicia Yang, Benjamin S. Bleier, Mansoor M. Amiji
Abstract
INTRODUCTION: Nose-to-brain drug delivery provides a promising noninvasive route to bypass the blood-brain barrier through direct nasal cavity-brain connections. Therapeutic agents reach the central nervous system via systemic circulation or olfactory/trigeminal nerve pathways. Only the olfactory epithelium enables direct brain transport through olfactory neurons, bypassing the blood-brain barrier, while the respiratory epithelium primarily supports systemic absorption before CNS access via trigeminal nerves. AREAS COVERED: This review examines anatomical and functional differences between olfactory and respiratory epithelia, focusing on receptor, lectin, microbial, and enzymatic expression variations, particularly species-specific differences. These distinctions create opportunities for selective olfactory epithelium targeting. Key studies using formulation strategies and physical delivery methods to enhance olfactory-specific drug delivery are discussed, alongside analytical techniques for assessing olfactory accumulation. A systematic literature search across major databases through June 2025 supports these findings. EXPERT OPINION: Despite decades of research, nose-to-brain drug delivery faces unresolved challenges. Major limitations include imprecise targeting of the olfactory epithelium and the lack of standardized in vitro and in vivo models for determining exact transport mechanisms and enabling cross-comparisons. Addressing these gaps is essential for advancing targeted nose-to-brain drug delivery systems.