Improved drug delivery across the blood-brain barrier through post-insertion functionalization of lipid nanocapsules with cannabidiol using click chemistry
Year: 2026
Type: article
Abstract: 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
Institutions: Universidad Complutense de Madrid, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Universidad de Zaragoza, Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, Instituto de Nanociencia y Materiales de Aragón, Cooperativa de Ensino Superior Politécnico e Universitário
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $3,790
Funders: Banco Santander, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, Universidad Complutense de Madrid, Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Universidade do Porto, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, Fundação para a Ciência e a Tecnologia
OpenAlex ID: W7155074249