Innovations in Intranasal Nanocarrier Drug Delivery: Bridging the Gap Across the Blood-Brain Barrier

Abstract: Nose-to-brain drug delivery has emerged as a promising strategy for enhancing the transport of therapeutic agents to the Central Nervous System (CNS), particularly for drugs exhibiting poor brain bioavailability and limited permeability across the Blood-Brain Barrier (BBB). This non-invasive approach enables direct drug transport from the nasal cavity to the brain through the olfactory and trigeminal neural pathways, thereby bypassing the BBB and minimizing systemic drug exposure. Consequently, N2B delivery offers rapid onset of action while reducing peripheral adverse effects. Recent advancements in nanotechnology have significantly accelerated the development of intranasal drug delivery systems. A wide range of nanocarriers, including nanoemulsions, microemulsions, polymeric micelles, lipid-based nanoparticles, liposomes, and transfersomes, have been extensively investigated for their ability to improve drug delivery to the brain. These nanoscale carriers enhance the solubility, physicochemical stability, and nasal mucosal permeability of therapeutic molecules, resulting in improved drug absorption and targeted brain delivery. Furthermore, nanocarrier-based systems can overcome several physiological barriers, including the BBB, hepatic first-pass metabolism, and gastrointestinal enzymatic degradation, thereby improving the bioavailability of drugs that are otherwise difficult to administer effectively. In addition, the non-invasive nature of intranasal administration contributes to better patient compliance compared with parenteral routes such as intravenous injection. Despite these advantages, several challenges continue to limit the clinical translation of nose-to-brain drug delivery. Rapid mucociliary clearance, restricted drug-loading capacity, formulation stability, and the potential redistribution of drugs from the brain into the systemic circulation remain significant obstacles. To address these limitations, researchers are exploring innovative formulation strategies, including the incorporation of mucoadhesive polymers, surface functionalization, ligand-mediated targeting, and stimuli-responsive nanocarriers, to prolong nasal residence time and enhance drug uptake into the brain. Equally important are the safety and toxicological considerations associated with repeated intranasal administration of nanocarrier systems, highlighting the need for comprehensive preclinical evaluation and well-designed clinical studies to establish their long-term efficacy and safety. Overall, nanocarrier-assisted nose-to-brain drug delivery represents a transformative platform for the management of central nervous system disorders. By enabling direct, targeted, and efficient drug transport to the brain while reducing systemic exposure, this approach has the potential to overcome the limitations of conventional drug delivery systems and improve therapeutic outcomes for a wide range of neurological diseases.