<p>Depression, ranked as the fourth leading cause of disability worldwide, is typically treated with oral antidepressants. However, the inability of this treatment to achieve the intended effect prompts the search for alternative methods. The aim of this research was to develop a paroxetine HCl-loaded lipid-polymer-based nanoparticulate drug delivery system for depression treatment via intranasal administration. Lipid-polymer hybrid nanoparticles were synthesized by using a modified double-emulsion solvent evaporation method and characterized in terms of physicochemical properties. The permeability and cytotoxicity of the nanoparticles were investigated on the Caco-2 cell line. The developed lipid-polymer-based nanoparticles were functionalized with chitosan to enhance the permeability of the nanoparticles through the blood–brain barrier. The optimum nanoparticle formulation was achieved at about 300&#xa0;nm and a low polydispersity index. Paroxetine HCl, a highly water-soluble drug, was encapsulated into nanoparticles with an encapsulation efficiency of 77.144%. The cationic nanoparticles exhibited mucoadhesive characteristics, which support the permeability through the Caco-2 cell monolayer. Consequently, the proposed nanoformulation exhibited significant potential for treating depression intranasally.</p>