Enhancing the Antidepressant Efficacy of Quercetin via Brain-Targeted Lipid Nanocarriers: Fabrication,...

This study aims to develop a quercetin-loaded nanoparticles (QNP) with enhanced brain delivery capacity, which enables efficient delivery of quercetin to target brain regions under the guidance of borneol for the treatment of depression.

We prepared QNP via the thin-film dispersion method and characterized them by particle size, polydispersity index (PDI), zeta potential, morphology, release profile, and stability. Subsequently, a suite of models and assays including hemolysis test, cellular CCK-8 assay, cellular uptake experiment, and lipopolysaccharide (LPS) induced BV2 cell stress model were employed to comprehensively assess the antidepressant activity of QNP. Finally, we validated the in vivo antidepressant effect of QNP using an established depression mouse model.

QNP exhibit a spheroidal shape with favorable particle size, PDI, and zeta potential. They have high encapsulation efficiency and exhibit sustained drug release capability. QNP remain stable in serum and saline solution. They maintain stability after 30 days of storage at room temperature. Results from the hemolysis test and cellular CCK-8 assay preliminarily suggested that QNP had a favorable safety profile. Additionally, cellular uptake experiments showed that the uptake rate of QNP by cells was nearly twice that of the quercetin. Assays using corticosterone- and hydrogen peroxide-induced PC12 cell injury models demonstrate that QNP exert a concentration-dependent cytoprotective effect. In the LPS-induced BV2 cell stress model, QNP exhibit superior inhibitory activity against NO and ROS compared with Qu. They also significantly inhibit IL-1β transcription. In vivo studies indicated that, compared with the first-line antidepressant fluoxetine, QNP alleviated depressive-like behaviors more effectively.

The lipid nanodrug delivery system QNP exhibit sustained drug release and enhanced cellular uptake. By virtue of safety and improved delivery efficiency, they multidimensionally augment the therapeutic efficacy of antidepressants. This is crucial for translating quercetin from a dietary supplement into a precision antidepressant.