PEGylated Nanoparticles Bind to and Alter Amyloid-Beta Peptide Conformation: Toward Engineering of Functional Nanomedicines for Alzheimer’s Disease

We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aβ_1–42) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the interaction with monomeric and soluble oligomeric forms of Aβ_1–42 peptide was demonstrated by capillary electrophoresis, surface plasmon resonance, thioflavin T assay, and confocal microscopy, where the binding affected peptide aggregation kinetics. The capture of peptide by NPs in serum was also evidenced by fluorescence spectroscopy and ELISA. Moreover, <i>in silico</i> and modeling experiments highlighted the mode of PEG interaction with the Aβ_1–42 peptide and its conformational changes at the nanoparticle surface. Finally, Aβ_1–42 peptide binding to NPs affected neither complement activation in serum nor apolipoprotein-E (Apo-E) adsorption from the serum. These observations have crucial implications in NP safety and clearance kinetics from the blood. Apo-E deposition is of prime importance since it can also interact with the Aβ_1–42 peptide and increase the affinity of NPs for the peptide in the blood. Collectively, our results suggest that these engineered long-circulating NPs may have the ability to capture the toxic forms of the Aβ_1–42 peptide from the systemic circulation and potentially improve Alzheimer’s disease condition through the proposed “<i>sink effect</i>”