Ginseng-loaded nanostructured lipid gels for nose-to-brain targeted modulation of 5-HT receptors in cognitive disorders

This research sought to enhance the bioavailability and brain delivery of ginseng, a conventional herbal remedy with therapeutic potential for cognitive impairments, which is limited by poor oral bioavailability and brain penetration. Ginseng-loaded lipid nanoparticles (LNPs) were formulated using a thermal emulsification technique followed by probe sonication. The resultant nanocarriers were characterized with respect to particle size distribution, zeta potential, and stability. The optimized lipid nano-carrier (LNC) was integrated into an in situ gel system and evaluated for its physicochemical properties, muco-adhesion, and permeation through a nasal epithelial cell model. In silico docking studies indicated significant interactions between ginsenosides and the 5-hydroxytryptamine receptor, suggesting a possible mechanism for cognitive enhancement. Confocal laser scanning microscopy (CLSM) and in vivo investigations were conducted to support these findings. The ginseng-loaded LNPs demonstrated a particle size distribution between 178 nm and 213 nm, with a negative zeta potential (-9.07) and an encapsulation efficiency of 79.58 %. Docking studies showed a promising docking score of −7, highlighting the binding potential of ginsenosides with the 5-HT receptor. The in situ gel system facilitated sustained release of ginseng and significantly enhanced permeation through the epithelial layer compared to a ginseng suspension. In vivo investigations demonstrated that the ginseng concentration in the CNS was 3.5 times higher in the groups administered the ginseng-loaded NLC in-situ gel than in those given a simple ginseng suspension. The ginseng-encapsulated NLC in-situ gel system shows potential for enhanced cerebral delivery and cognitive enhancement, offering a promising strategy for treating cognitive disorders. • Innovative delivery system: Ginseng-loaded lipid nanoparticles in an in situ gel improved bioavailability and brain delivery. • Improved nanoparticle properties: Nanoparticles showed 178–213 nm size, negative zeta potential, and 79.58% entrapment efficiency. • Enhanced permeation and release: In situ gel enabled sustained release and significantly improved nasal ginseng permeation vs suspension. • Cognitive enhancement mechanism: Docking showed strong ginsenoside–5-HT receptor binding (score −7), suggesting cognitive benefits. • Superior brain delivery: In vivo studies showed a 3.5-fold higher CNS ginseng level with NLC in situ gel vs suspension.