Berberine chloride-loaded polymeric lipid hybrid nanoparticles ameliorate cognitive impairment by reducing phosphorylation of tau at threonine 231.

Berberine chloride-loaded polymeric lipid hybrid nanoparticles (BBC-PLPNPs) were developed and surface-functionalized with transferrin (TBBC-PLPNPs) for targeted brain delivery in Alzheimer's disease therapy. The optimized nanoparticles showed a size of 272 ± 14 nm, PDI < 0.3, and zeta potential of -12.0 ± 1.9 mV. Entrapment efficiency and drug loading were 91.2 ± 7.6% and 7.10 ± 1.53%, respectively. Morphological and structural studies confirmed spherical shape and amorphous nature. In vitro assays demonstrated sustained drug release, antioxidant activity, and inhibition of amyloid-beta fibril formation. Pharmacokinetic analysis revealed enhanced brain delivery with significantly higher MRT (5.12 ± 0.16 h), AUC₀-₂₄ (8.90 ± 0.34 h*μg/L), and brain accumulation in TBBC-PLPNP-treated rats (***p < 0.001). In vivo, TBBC-PLPNPs significantly improved OKA-induced cognitive deficits and reduced p-Tau 231 levels (**p < 0.01) in C57BL/6 mice. These results highlight the potential of TBBC-PLPNPs as an effective brain-targeted nanocarrier for Alzheimer's disease therapy.