Peptide functionalization of a brain-targeting hybrid nanocarrier for enhanced drug transport in Alzheimer's disease

Abstract

To address the limited transport of therapeutics across the blood–brain barrier (BBB) in Alzheimer's disease (AD), we engineered brain targeting inorganic hybrid nanoparticles (TNP) capable of co-delivering curcumin (CUR) and quercetin (QUER) for AD treatment. TNP were surface functionalized with angiopep-2 via biotin–streptavidin interaction. The angiopep-2 peptide facilitates selective interaction with low-density lipoprotein receptor-related protein 1 (LRP1) expressed on endothelial cells, promoting receptor-mediated transport across the BBB. Additionally, angiopep-2 can promote the transport of drug loaded nanoparticles to affected neural cells by binding to LRP1, thereby enhancing drug accumulation in pathological regions of Alzheimer's disease. Compared with the free drugs, the co-delivery system CUR/QUER@TNP exerts neuroprotective effects, including antioxidant activity, inhibition of apoptosis, suppression of amyloid-β aggregation and modulation of tau protein phosphorylation, more effectively in SH-SY5Y cells. These results indicate that the brain targeting delivery system improves neuroprotective efficacy and leads to a more pronounced reduction in tau-associated pathology. Our study demonstrates that the inorganic hybrid nanocarrier can serve as an effective platform for enhancing brain drug delivery, thereby offering a promising avenue for AD therapy. This functionalization strategy, based on the biotin–streptavidin interaction, offers a facile and universal approach for the convenient incorporation of other targeting ligands.