The Nasal-Brain Drug Delivery Route: Mechanisms and Applications to Central Nervous System Diseases

Abstract

The blood-brain barrier (BBB) is a highly selective and protective barrier that restricts the entry of most therapeutic agents into the central nervous system (CNS), posing a significant challenge for the treatment of CNS diseases. The nose-to-brain drug delivery (NBDD) route has emerged as a promising strategy to bypass the BBB, offering direct, noninvasive, and efficient transport of drugs to the brain. This review begins with a concise overview of the BBB structure and its biofunctions, followed by an in-depth discussion of the mechanisms underlying the nose-to-brain pathway, including the olfactory and trigeminal nerve routes, and respiratory pathway. We further highlight the therapeutic research development of neurodegenerative diseases, acute neurological diseases, brain tumor, and psychiatric disorders when using NBDD drugs encompassing small-molecule drugs, proteins, peptides, nucleic acids, siRNA, and herbal compounds, in which we also introduce innovative delivery systems, including nanocarriers and novel platforms such as exosomes, which enhance drug stability, targeting efficiency, and bioavailability. In addition, we provide a comprehensive overview of recent clinical advancements in therapeutics delivered via the intranasal route for CNS diseases. Finally, we discuss the challenges and future directions of NBDD, emphasizing its potential to transform the treatment landscape for CNS disorders.

Keywords: blood–brain barrier; central nervous system diseases; drug delivery systems; intranasal administration; nose–brain drug delivery.

FIGURE 1

Schematic representation of the blood–brain barrier (BBB) in normal brain and the diseased BBB under pathological conditions. The BBB is composed of endothelial cells connected by tight junctions, supported by pericytes and astrocytes. In neurological diseases, the BBB undergoes structural and functional alterations, including increased permeability due to tight junction loss, enhanced transcytosis from reduced MFSD2A and/or increased caveolin‐1 expression, and impaired carrier‐mediated transport and receptor‐mediated transport functions. Additionally, cellular infiltration and degeneration of pericytes and endothelial cells contribute to BBB disruption. MFSD2A: major facilitator superfamily domain‐containing protein 2a.

FIGURE 2

The pathways and mechanisms for nose‐to‐brain delivery. (A) Schematic diagram of the internal structure of nasal cavity and three routes of nasal brain administration. After nasal administration, some drugs undergo mucociliary clearance and enzymatic degradation in the nasal mucosa before reaching systemic and central nervous system (CNS) compartments. Drugs in the respiratory region near the inferior turbinate are absorbed into the bloodstream via the respiratory pathway. The nose‐to‐brain pathway primarily involves the olfactory and trigeminal nerve routes, as well as the respiratory pathway, which includes axonal transport through olfactory and trigeminal nerves. (B) The major components of the olfactory epithelium and lamina propria, along with the uptake routes from the nasal cavity. The olfactory region comprises the olfactory epithelium (OE) and lamina propria. The OE is surrounded by globose and horizontal basal cells and includes sustentacular cells, Bowman's glands (which produce mucus), and olfactory sensory neurons. The lamina propria, separated from the OE by a basal lamina, contains blood and lymphatic vessels. Drug transport across the epithelium can occur via paracellular or transcellular pathway, allowing molecules to pass through tight junctions or cells to reach the lamina propria. From there, drugs can enter systemic circulation via blood or lymphatic vessels. Additionally, olfactory sensory neurons provide a direct intracellular pathway for brain delivery.