The olfactory epithelium as a gateway for bloodborne nanoparticles to the central nervous system

While transnasal nanoparticle (NP) mucosal uptake is well-documented, recent studies suggest that some NPs and viruses can also enter the central nervous system (CNS) through systemic circulation without disrupting blood-brain barrier (BBB) integrity. Here, we used T₁-weighted MRI, ICP-AES analysis and optical tomography to track the distribution of 50 nm Mn₃O₄-NPs and 130 nm polyelectrolyte layer-by-layer capsules labeled with Cy7 and gold NPs (LbL-Au) in mouse brains following intravenous or intranasal administration. The olfactory epithelium (OE) served as a critical gateway for blood-to-brain NP transport, mediating CNS entry through distinct intracellular and paracellular pathways. Pharmacological inhibition of axonal transport (colchicine, 10 μg μl^-1) and chemical ablation of the OE (ZnCl₂, 5%) completely blocked Mn₃O₄-NP accumulation in olfactory pathways (olfactory bulb, olfactory tract, and cortical targets), while permitting unaltered deposition in the adenohypophysis, confirming an olfactory neuron-dependent transport mechanism. In contrast, LbL-Au translocation was abolished by epithelial ablation but unaffected by axonal transport inhibition, demonstrating predominant paracellular passage. Notably, both intranasal and intravenous administration routes resulted in NP deposition within the OE and subsequent brain delivery, revealing route-independent olfactory uptake. These findings establish the OE as a dual-pathway hub for systemic NPs, facilitating CNS entry via intracellular axonal transport (Mn₃O₄-NPs) or paracellular mechanisms (LbL-Au). By demonstrating that blood-borne NPs can exploit olfactory pathways to bypass the BBB, this work challenges traditional models of CNS xenobiotic entry and opens new avenues for targeted neurotherapeutic delivery.