Shape and Surface Modification Dependent Cellular Interactions of Gold Nanoparticles in a 3D Blood-Brain Supported Neurospheroid Model

Abstract

Recent investigations have begun to explore the cellular interactions of nanoparticles (NPs) in three-dimensional (3D) neuro-spheroid models of the blood-brain barrier (BBB), offering novel insights into NP transport across the barrier and their potential neurotoxic effects. Building on these findings, we investigated the effects of particle shape and surface modification on the transport dynamics and cellular interactions of gold NPs (AuNPs) using a multicellular 3D spheroid model of the BBB. AuNPs with two different morphologies, spherical and rod-like, were synthesized, modified with polyethylene glycol (PEG) and characterized in detail using Ultraviolet-Visible (UV-Vis) Spectroscopy, Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) techniques. A 3D neuro-spheroid model consisting of mouse brain endothelial cells (bEnd.3), motor neuron-like hybrid cells (NSC-34) and glial cells (C6) was employed to evaluate the BBB transport characteristics and cytotoxicity of bare and PEG-coated spherical and rod-shaped AuNPs. Our results indicated that 3D neurospheroid models can serve as orchestral platforms for studying cellular behaviour of NPs. PEGylation of NPs substantially reduced cytotoxic effects compared to bare particles. While spherical AuNPs showed limited translocation through the endothelial barrier, those that entered the spheroid were found to be distributed deeper within the interior. In contrast, rod-shaped particles exhibited a greater capacity to cross the BBB but tended to accumulate near the periphery without deeper penetration. These findings underscore the critical role of shape and surface chemistry in nanoparticle-mediated BBB transport and support the utility of 3D neuro-spheroid models in predicting nanoparticle behavior in brain tissue.