Tween 80-Modified Chitosan Nanoparticles via Ionotropic Gelation for Enhanced Brain Delivery of Chrysin and Improved Anxiolytic Efficacy in Preclinical Models

The natural polyphenol “Chrysin,” an antianxiety compound, has limited brain uptake due to the restricted crossing of the blood–brain barrier (BBB). In this study, we formulated Chrysin-encapsulated chitosan nanoparticles (CNPs) and Tween 80-coated CNPs (cCNPs) to improve Chrysin’s uptake in the brain and enhance the antianxiety effects. The CNP and cCNP nanoformulations were physicochemically characterized for calculating their particle size, polydispersity index (PDI), drug entrapment efficiency (EE %), and zeta potential. Further, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and in vitro release studies were performed. The obtained results indicated the reduced particle size of cCNP NPs (174.40 ± 2.51 nm) compared to CNPs (197.67 ± 4.94 nm) and showed an increased EE for cCNPs (86.8%) compared to CNPs (82.73%). The zeta potential of cCNPs was calculated to be −14.4 ± 1.20 mV, in contrast to +12.3 ± 0.50 mV for CNPs. TEM images exhibited the presence of spherical cCNPs. In vivo studies revealed a higher time in the light compartment in the light–dark model and increased time spent in the open arm in elevated and maze models. This demonstrates significantly enhanced antianxiety effects of cCNPs compared to CNPs and pure Chrysin. These findings were further validated by the significant reduction in plasma nitrite levels, without any impact on locomotor activity. Additionally, histopathological evaluation of liver, kidney, and brain tissues confirmed the safety of cCNPs, with no significant structural changes observed. This study augments the therapeutic efficacy of cCNPs through enhanced brain uptake by reduced particle size and facilitating adsorptive transcytosis.