Engineered PLGA Nanoparticles for Brain-Targeted Codelivery of Cannabidiol and pApoE2 through the Intranasal Route for the Treatment of Alzheimer’s Disease

Neuroinflammation induced by the accumulation of amyloid beta plaques expedites the progression of Alzheimer's disease (AD). Reducing Aβ plaques and associated neuroinflammation could potentially help to delay the progression of AD. Cannabidiol (CBD) is well-known for its antioxidant, anti-inflammatory, and neuroprotective nature, and the ApoE2 is effective in binding and clearing Aβ plaques in the brain. Therefore, codelivery of CBD and pApoE2 to the brain would be a promising therapeutic approach in developing effective therapeutics against AD. This research aims to design a nonviral delivery agent that delivers both drugs and genes to the brain through a noninvasive intranasal route. We have developed mPEG-PLGA nanoparticles coated with mannose, a brain-targeting ligand, to deliver CBD and pApoE2. The designed CBD-loaded coated nanoparticles showed an average diameter of 179.3 ± 4.57 nm and a zeta potential of 30.3 ± 6.45 mV. The coated nanoparticles prolonged the CBD release and showed a 93% release of its payload in 30 days. CBD-loaded nanoparticles, as compared to the free CBD, significantly reduced lipopolysaccharide and amyloid beta-induced inflammation in immortalized microglia cells. Cytotoxicity of the designed nanoparticles was assessed against brain endothelial cells (bEND.3) and found to be nontoxic in nature. The mannose-conjugated chitosan-coated nanoparticles were cationic and able to bind with the pApoE2, protecting the encapsulated pApoE2 from enzymatic degradation. Quantitative in vitro transfection efficiency study in primary astrocytes and primary neurons revealed that the ApoE2 expression level is significantly (<i>P</i> < 0.0001) higher for mPLGA-CBD-MC/pApoE2 than the control. The ApoE2 expression level in the brain of C57BL6/J mice was significantly (<i>P</i> < 0.0001) increased after intranasal administration of mPLGA-CBD-MC/pApoE2. Henceforth, the mannose-conjugated chitosan-coated mPLGA nanoparticles could serve as a nonviral delivery system to deliver both drugs and genes to the brain through the intranasal route for the management of AD.