Crossing the blood-brain barrier (BBB) remains a major challenge in drug delivery for central nervous system (CNS) diseases. This study presents a covalent functionalization strategy to attach cannabidiol (CBD), the major non-psychotropic phytocannabinoid, to lipid nanocapsules (LNCs) to enhance their BBB permeability in vitro and in vivo . Using click chemistry, two highly monodisperse CBD-functionalized LNC formulations are prepared, LNC1CBD and LNC2CBD, with sizes of 27.0 ± 0.8 nm and 55.0 ± 2.5 nm, and functionalization efficiencies of 30.82 ± 5.93% and 29.59 ± 8.34%, respectively. LNC2CBD exhibits a 55.77% increase in cellular uptake relative to non-functionalized LNCs. In vitro permeability assays demonstrate that LNC1CBD significantly enhances translocation across the healthy BBB at earlier timepoints (4, 8 and 12 h), whereas LNC2CBD exhibits enhanced permeability at later stages (12 and 24 h) compared to their non-functionalized counterparts. This trend is maintained in a diseased BBB model, where CBD functionalization significantly improves permeability at nearly all timepoints for both formulations. Biodistribution studies in healthy mice validate these findings, revealing a consistent in vitro - in vivo correlation. LNC1CBD significantly increases brain accumulation by 14.87% at 30 minutes, while LNC2CBD maintains this effect, reaching 17.64% at 30 minutes, 38.23% at 90 minutes and 73.53% at 240 minutes, relative to non-functionalized LNCs. These findings underscore the potential of LNCs covalently functionalized with CBD as a promising platform for CNS-targeted delivery, which can ultimately open new avenues for therapeutic agents that do not usually reach the brain parenchyma at effective concentrations. • Cannabidiol (CBD) is covalently conjugated to lipid nanocapsules via click chemistry • Decoration with CBD enhances blood–brain barrier permeability in vitro and in vivo • Particle size critically influences brain accumulation of lipid nanocapsules • CBD-functionalized lipid nanocapsules represent a versatile platform for brain drug delivery
Pérez-López et al. (Wed,) studied this question.