Lactoferrin-Anchored Carboxymethyl Pullulan-MgO Nanocomposites for Targeted Delivery of Trans-Ferulic Acid: Physicochemical Characterization, In vitro and Ex vivo Studies

The design of efficacious nanotherapeutics for neurodegenerative disorders necessitates the development of precisely targeted delivery systems capable of transversing the blood-brain barrier (BBB) while sustaining therapeutic efficacy. Here, we introduce a novel brain-targeted nanocomposite system comprising carboxymethylated pullulan-magnesium oxide (CMP-MgO) matrix encapsulating trans-ferulic acid (TFA) and last surface-functionalized with lactoferrin (Lf) to facilitate receptor-mediated transcytosis. Comprehensive physicochemical characterization, including dynamic light scattering (DLS), proton-nuclear magnetic resonance (¹H NMR), fourier transform infrared (FT-IR), high resolution-transmission electron microscopy (HR-TEM), atomic force microscopy (AFM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and circular dichroism (CD) spectroscopy, confirmed the structural integrity functionalization, and stability of the nanocomposites. DLS studies exhibited a hydrodynamic diameter of 386 ± 5.06 nm, a polydispersity index of 0.087 ± 0.008, and a zeta potential of -20.5 ± 0.19 mV of the Lf-TFA-CMP-MgO. Morphological analysis confirmed spherical particles with a smooth surface, and CD spectroscopy confirmed the perpetuation of the native structure of Lf after conjugation with the nanocomposite. The antioxidant assay highlighted significant free radical scavenging activity, reflecting the antioxidant potential of TFA and TFA-loaded nanocomposites. <i>In vitro</i> studies demonstrated excellent biocompatibility and enhanced cellular internalization due to Lf functionalization. Notably, the nanocomposite inhibited amyloid fibril formation by interacting with hen egg white lysozyme (HEWL). Furthermore, intranasal delivery achieved efficient nose-to-brain transport, with permeability of 415.45 μg/cm² at 6 h, highlighting its mucoadhesive properties and noninvasive therapeutic capability for Alzheimer's disease (AD).