Nose-to-brain delivery of IRX4204 by cell-adhesion peptide-functionalized gemini surfactant-phospholipid...

Efficient delivery of hydrophobic therapeutics to the central nervous system (CNS) remains challenging due to poor solubility, limited blood-brain barrier permeability and systemic toxicity. Here, we report the development of gemini surfactant-phospholipid nanoparticles (GPNPs) for intranasal delivery of the highly potent and preferential retinoid X receptor agonist IRX4204. Physicochemical characterization demonstrated stable nanoparticles (60 nm, +40 mV) with high encapsulation efficiency and long-term stability. Dynamic light scattering, transmission electron microscopy and small-angle X-ray scattering revealed that optimal drug loading in GPNPs is ≤0.5 mg mL^-1. The formulations showed the coexistence of two structurally distinct particle populations, flattened micelles and larger vesicular structures. In vivo studies in mice demonstrated that intranasal administration of IRX4204-GPNPs (0.12 mg kg^-1) achieved higher CNS concentrations than a 100-fold higher oral dose (12 mg kg^-1), with sustained distribution across various CNS regions and enhanced striatal accumulation. Compared to oral IRX4204 suspension administration, intranasal delivery of IRX4204-GPNPs achieved about 1.4-fold higher CNS drug concentrations, 136-fold greater delivery efficiency (0.19% vs. 0.0014% of dose) and 73.5% direct transport percentage (DTP), accompanied by markedly reduced plasma and liver exposure. Pharmacodynamic evaluation confirmed sustained activation of RXR-responsive genes, including SCD1 and LXRα, following intranasal nanoparticle delivery. These findings demonstrate that optimized GPNPs enable efficient CNS targeting and support their use as a promising intranasal platform for delivery of RXR agonists and other hydrophobic therapeutics.