The Nose‐To‐Brain Transport of Polymeric Nanoparticles Is Mediated by Immune Sentinels and Not by Olfactory Sensory Neurons

Abstract The nose‐to‐brain (N‐to‐B) transport mechanism of nanoparticles through the olfactory epithelium (OE) is not fully understood. Most research utilized nasal epithelial cell models completely deprived of olfactory cells. Aiming to shed light into key cellular pathways, in this work, for the first time, the interaction of polymeric nanoparticles in a 17–483 nm size range and with neutral and negatively and positively charged surfaces with primary olfactory sensory neurons, cortical neurons, and microglia isolated from olfactory bulb (OB), OE, and cortex of newborn rats is investigated. After demonstrating the good cell compatibility of the different nanoparticles, the nanoparticle uptake by confocal laser scanning fluorescence microscopy is monitored. Our findings reveal that neither olfactory nor forebrain neurons internalize nanoparticles. Conversely, it is demonstrated that olfactory and cortical microglia phagocytose the nanoparticles independently of their features. Overall, our findings represent the first unambiguous evidence of the possible involvement of microglia in N‐to‐B nanoparticle transport and the unlikely involvement of neurons. Furthermore, this approach emerges as a completely new experimental tool to screen the biocompatibility, uptake, and transport of nanomaterials by key cellular players of the N‐to‐B pathway in nanosafety and nanotoxicology and nanomedicine.