Chitosan-Modified Biodegradable Polymeric Nanoparticles for Tunable Cannabidiol Release and Enhanced Mucosal Transport

Mucosal drug delivery offers an attractive approach for localized and systemic therapy while bypassing first-pass metabolism; however, its success is often hindered by poor drug permeability, rapid clearance, and low bioavailability. In this study, we developed a sustainable cannabidiol (CBD)-loaded nanocarrier system based on poly(D, L-lactide-co-glycolide) (PLGA) nanoparticles surface-modified with chitosan (CS), a renewable biopolymer, to enhance mucosal and neurodegenerative therapeutic performance. CS-coated PLGA nanoparticles (50–2000 µg/mL) exhibited increased particle size, a positive surface charge, and improved hydrophilicity, enabling stronger mucoadhesive interactions and storage stability for at least six months. Although CS modification slightly reduced encapsulation efficiency and drug loading, it markedly improved sustained and controlled CBD release by reducing burst effects and prolonging drug retention, consistent with first-order and Higuchi kinetics. Enhanced mucoadhesion was confirmed through stronger electrostatic interactions with mucin and improved rheological behaviour, promoting longer mucosal residence time and greater bioavailability. All formulations were highly biocompatible in HT-29 cells and exhibited significant anti-inflammatory activity, with CS-modified systems showing superior nitric oxide inhibition. Remarkably, CS-modified PLGA-CBD nanoparticles demonstrated potent, dose-dependent anti-amyloidogenic activity, outperforming curcumin at low to moderate concentrations, highlighting their promise as multifunctional, environmentally responsible nanocarriers for mucosal drug delivery and neuroinflammatory disease management.