Nose-to-brain drug delivery: A new frontier in targeted therapeutics.

Delivering therapeutics to the Central Nervous System (CNS) remains a major challenge in drug development, largely because the blood-brain barrier (BBB) limits brain exposure for most systemically administered agents. Among alternative delivery routes, intranasal administration has attracted significant interest because it leverages direct anatomical connections between the nasal cavity and the brain, thereby reducing reliance on BBB permeability. This review examines the nasal route, focusing on how olfactory and trigeminal neural pathways contribute to drug transport into the CNS. Rather than assuming a single dominant route, the relative roles of extracellular perineural diffusion, intracellular neuronal transport, perivascular movement, and cerebrospinal fluid-associated distribution are evaluated in light of existing experimental evidence. Key factors that limit or enhance intranasal brain delivery-including mucociliary clearance, local enzymatic activity, drug physicochemical properties, formulation design, and patient-specific variability-are discussed with attention to their practical implications. Recent advances in formulations, such as mucoadhesive and in situ gelling systems, particulate and lipid-based carriers, dendrimers, and stimuli-responsive platforms, are reviewed alongside developments in nasal delivery devices that influence regional deposition.