In Vitro Investigation of Glucosylceramide-Mediated Brain-Targeting in Water-in-Oil-in-Water Nanoemulsions Containing Astaxanthin, Curcumin, and Sesame Oil.

Brain delivery of lipophilic antioxidants is limited by poor solubility and restricted transport across the blood-brain barrier (BBB). To address this challenge, we developed a plant-derived glucosylceramide (GlcCer)-based w/o/w nanoemulsion designed to exploit glucose transporter (GLUT)-mediated uptake for brain targeting. Unlike synthetic glucose conjugates, GlcCer provides intrinsic amphiphilicity and biocompatibility, enabling self-assembly into stable, surfactant-free nanoemulsions incorporating astaxanthin, curcumin, and sesame oil through a cost-effective and scalable process. The resulting GlcCer-functionalized nanoemulsions demonstrated enhanced physicochemical stability and low cytotoxicity in SH-SY5Y and hCMEC/D3 cells. Quantitatively, the sesame oil-based targeted formulation achieved a 1.6-fold increase in neuronal uptake, stronger ROS suppression, and a 1.4-fold improvement in transendothelial transport compared with nontargeted controls. These findings identify GlcCer-based w/o/w nanoemulsions as a promising and scalable platform for brain-targeted antioxidant delivery.