NANOPARTICLE-BASED INTRANASAL DELIVERY SYSTEMS FOR BRAIN TARGETING IN DEPRESSION: MECHANISMS, THERAPEUTIC OUTCOMES, AND TRANSLATIONAL CHALLENGES

Depression is still one of the most severe worldwide health disorders, with conventional oral antidepressant medications hampered by delayed onset, significant first-pass metabolism, low adherence, and limited brain penetration. This review critically assesses nanoparticle-based intranasal delivery options designed to address these constraints. Intranasal injection allows for direct nose-to-brain transport via the olfactory and trigeminal pathways, which bypasses the blood-brain barrier and hepatic metabolism. However, traditional intranasal formulations confront problems such as enzymatic breakdown, mucociliary clearance, and a short nasal residence period. Nanocarrier systems, which include polymeric, lipid-based, and inorganic nanoparticles, improve drug solubility, stability, mucosal retention, penetration, and controlled release. Mucoadhesive coatings like chitosan enhance residence duration and paracellular transfer. In recent preclinical investigations, antidepressant-loaded nanoparticles have shown significant pharmacokinetic and pharmacodynamic advantages, such as higher brain bioavailability, faster start of action, and improved behavioral results. Despite these advancements, clinical translation is still limited due to safety, regulatory, manufacturing, and evaluation constraints. This review summarizes current findings, highlights significant knowledge gaps, and proposes future paths to aid in the development of therapeutically applicable nanoparticle-based intranasal antidepressants.