Abstract

Gold nanoparticles (GNP) are highly valuable in nanotechnology due to their biocompatibility and unique physicochemical properties, which make them attractive as nanocarriers for targeted drug delivery. In the context of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), GNP hold promise for reducing the toxicity of Amyloid-? peptide (A?) aggregates. However, a major challenge in developing new therapies for NDDs lies in the limited reliance on animal models and the difficulty of crossing the blood-brain barrier (BBB). This study investigates the effects of GNP on A? toxicity using a human-based BBB-organ-on-a-chip model (BBB-oC), mimicking the 3D cellular architecture of the BBB under both normal and pathological conditions. We rationally designed a novel nanosystem functionalized with the peptide D3, which functions both as a selective A? toxicity inhibitor and a BBB-targeting agent. The results show that GNP can cross the BBB, reduce the A?-induced cytotoxicity, and promote the maintenance of the BBB integrity. Moreover, controlling the shape of GNP further enhanced their protective effect. Overall, this work highlights the feasibility of rationally designed GNP as a promising therapeutic strategy for AD, evaluated through a more reliable and predictive human-relevant model. © 2025