¹Department of Pharmaceutics, Marathwada Mitra Mandal’s College of Pharmacy, Pune-411033, India DOI : 10.29228/jrp.837 The current study aims to prepare agomelatine-loaded nanostructured lipid carriers (AGO-loaded NLCs) and their administration through the intranasal route in an attempt to circumvent hepatic metabolism, facilitate controlled release, and increase cerebral distribution, etc. Agomelatine faces several challenges such as a fast metabolic process, limited solubility, gastrointestinal vulnerability, enzymatic cleavage, and decreased bioavailability. These challenges collectively undermine its therapeutic effectiveness. Therefore, the goal of the current work is to develop agomelatine-loaded NLCs with enhanced drug entrapment, extended release, and improved stability. Agomelatineloaded NLCs were prepared by using Glyceryl monostearate and Neroli oil as solid lipid and liquid lipid respectively, While Tween 80 and poloxamer 188 were used as surfactant and co-surfactant. The technique of melt emulsification ultrasonication was employed to prepare these NLCs. The prepared formulation was optimized utilizing a three-factor, three-level Box-Behnken design with total lipid percentage, surfactant, and co-surfactant percentage, and ultrasonication time as independent variables and particle size, zeta potential, and percentage entrapment efficiency as dependent variables. The optimized NLCs size was found to be 122 ± 3.19 nm and the results from transmission electron microscopy are likewise within this size range (under 150 nm) and showed that the particles were homogeneous and nearly spherical, with porous and irregular surface features. Polydispersity index, zeta potential, entrapment efficiency, and drug release % were observed as 0.353 ± 0.15, -33.7 ± 2.35 mV, 90.57 ± 0.984% and 94.65 ± 2.39% respectively. The findings from the permeation study indicated a substantial enhancement in permeation for AGO-loaded NLCs when compared to AGO solution. Keywords : Agomelatine; Blood brain barrier; Box-Behnken design; Intranasal delivery; Nanostructured lipid carriers