**6. BBB and internalization pathways to the brain**

Although nanoparticles can enter different compartments of the organism and generate local toxicity, their presence in the brain has been the subject of multiple studies to elucidate the mechanisms for brain internalization as toxicity in the CNS can lead to the onset of neurodegenerative diseases.

Previous studies have identified a gradient of damage and accumulation of metals in the following direction, olfactory mucosa > olfactory bulb > frontal cortex [23], and the possible routes through which environmental pollutants reach the brain have been described [21].

Recent works [30] have mentioned the existence of distinct routes of post-exposure entry of nanoparticles into the nasal cavity, the trigeminal route, systemic route, and olfactory route. These entry routes present nanoparticles with compartments that differ in their cellular composition and structure, representing barriers for drug transport and delivery. Nanoparticles can reach the brain either bypassing the BBB or by axonal transport along the olfactory nerve and once there they can become toxic especially due to their increased surface area which increases chemical reactivity and biological activity [12].

Of the different types of nanoparticles that are frequently used in brain-related biomedical applications, titanium oxide, iron oxide, silver, gold, silica, and carbon nanoparticles have been described to exhibit neurotoxic effects ranging from oxidative stress to alterations of brain development in embryonic stages. However, changes in their surface area, size or morphology may have impacts on both the degree of toxicity and their beneficial effects; more extensive studies on their mechanisms of action including modification of gene expression are required to identify more suitable materials, for biomedical use [12, 31–33].

Recapitulating the various biomedical applications and specifically those related to the CNS, it is important to identify which nanomaterials are currently under study and to verify their toxicity which may arise from the accumulation of these materials in the brain, otherwise, they could not be considered for the clinical setting and their potential advantages could not be translated into concrete benefits for society.
