**1. Introduction**

Environmental pollution is silently responsible for millions of deaths worldwide, by the year 2060 it is expected to cause between 6 and 9 million deaths; surpassing even the deaths related to tobacco [1]. Exposure to air pollution has been linked to harmful effects on health such as cardiovascular diseases, ischemia, heart attacks, lung cancer and an may increase the risk and trigger neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. It is also related to the onset of childhood neurodevelopmental disorders such as attention deficit, autism and the onset of schizophrenia [1–5].

A diverse mixture of suspended matter or particulate matter (PM) including manmade nanomaterials, gases, and organic and inorganic compounds is found in environmental pollution; suspended matter can be classified according to aerodynamic diameter or particle size. Particles bigger than 2.5 μm are considered coarse particles, those smaller than 2.5 μm fine particles, and those smaller than 0.1 μm are classified as ultrafine particulate matter or ultrafine particles (UFP or UFPM for short) [3, 6]. The latter are of special interest due to their potential toxic effects since their small size and physicochemical properties give them the possibility of interacting with

different organs to which no other particle has access and, in addition, these interactions are different from those that the same material of a larger size could have. For example, their elimination can be considerably slowed down, which is linked to bioaccumulation for long periods exerting potentially harmful effects on the organism [1]. Specifically, their translocation to organs such as the heart, kidney, liver, or brain makes them a latent threat to public health; as it has already been recorded that they manage to cross biological barriers by various routes. In the case of the lungs and brain, the absorption of such particles can occur through the nasal mucosa causing systemic inflammation and oxidative stress on the central nervous system (CNS).

The most common entry routes of UFPs into the body are inhalation, dermal absorption, and ingestion, although the skin under proper conditions is an efficient barrier making the entry routes of greatest risk to the respiratory and gastric systems. The gastrointestinal tract is about 200 m2 of surface area lined with mucosa, represents a not very efficient barrier, despite the existence of cellular junctions that limit the passage of potentially harmful substances; since it allows the passage of practically any material below 500 nm (0.5 μm) [7]. It has been described that the junctions between epithelial cells can undergo modifications that facilitate the passage of ultrafine materials smaller than 15 nm allowing their arrival to the bloodstream and their consequent arrival to different organs including the brain [3]. The inhalation route, the respiratory system is divided into upper and lower airways, which represent two distinct pathways for particles that may be inhaled. The upper airways include the nose, nasal cavity, pharynx, and larynx; while the lower airways include the trachea and lungs including bronchi, bronchioles, and alveoli. The lung surface area is approximately 150 m2 and particles have the potential to cross the air-blood barrier into the bloodstream and disperse in the direction of other organs including the brain where again the blood-brain barrier (BBB) limits the free distribution of any potentially harmful substances [8]. As for the particles that remain attached to the nasal mucosa, there are two entry routes: particles can cross the respiratory epithelium reaching the blood vessels which gives them systemic access, or they can be absorbed by the epithelial cells and reach the brain in different forms of transport. It has been proposed that they may enter via the olfactory or trigeminal pathway through axonal transport, by paracellular transport by entering through the spaces between neuronal axons, or even that they could enter by transcellular or paracellular transport to the sustentacular olfactory epithelium [9].

An important problem is that these types of nanomaterials are not only found suspended in the air as part of the components of environmental pollution, but some of them are also similar in composition and characteristics to others used in biomedical areas for therapeutic purposes. Specifically, nanoparticles are materials that due to their characteristics have stood out in the development of applications in biomedicine due to their benefits and physical properties that are different from those of larger particles. Their dimensions are attractive for biomedical applications as they may show better clinical performance compared to conventional ways to deliver drugs or imaging tissues and organs [10]. However, these same characteristics give them the particularity of crossing barriers intended to protect us from potential toxic effects, such as the epithelial barrier of the skin, the gastrointestinal tract (GIT), the air-blood barrier of the lungs and even organ-specific barriers such as the blood-testicular barrier, the placental barrier, and the BBB [11]. The latter has the function of preserving the integrity of the CNS and cautiously selecting what can enter the CNS. When these barriers are breached by nanoparticles, they can be transported through the organism by systemic circulation, distributing and accumulating in different organs and tissues

without being correctly metabolized or eliminated by the organism, causing damage that does not necessarily depend on the dose but on their chronic permanence where they have been deposited [12].

Some of the most widely used nanoparticles for biomedical applications are magnetite (Fe3O4), carbon-based nanostructures (carbon nanotubes, graphene, carbon nanoparticles), silica (SiO2), as well as some metallic nanoparticles, in particular those containing silver (Ag) and gold (Au). Among the benefits derived from their use are improvements in imaging, creation of biosensors for disease detection (especially neurodegenerative diseases and cancer), targeted drug delivery, delivery of drugs to the brain and other relevant biomedical applications such as antiviral nanotherapeutics that could provide a rapid and efficient response to viruses causing pandemics such as the current one [13]. But to take advantage of the advances that nanomaterials offer and transfer them efficiently and safely to clinical application, it is necessary to identify those that present the best benefit-toxicity ratio, especially when it comes to materials with the ability to translocate and accumulate in the brain and potentially may cause neurodegenerative alterations.

Synthetic nanomaterials are manufactured for several technological applications in sectors such as agriculture, cosmetics, pharmaceuticals, engineering, the automotive industry, construction, among others. They can also be released to the environment after disposal and degradation of consumer items that contain them. Their potential environmental effects, caused by their diverse physical properties, are mostly unknown; one of the important problems of pollutant nanomaterials is their fate as they may end up being incorporated into bodies of water, food chains, and even the atmosphere where they can accumulate and be breathed [6, 14, 15].

There are also airborne nanoparticles coming from natural processes, such as volcanic ash, forest fires carbon particles, dust from natural wastes, fecal matter, decomposition of biological structures and several other sources. However, multiple human activities such as fires for land use, logging, mining, construction, overcrowding, etc., alter their natural cycles, incorporating large amounts of nanoparticles into the atmosphere in a short time, generating a considerable increase in their presence as part of environmental pollution [15].

As previously described, nanoparticles can cross the BBB and once inside can generate diverse toxic effects, such as inducing oxidative activity through the production of reactive oxygen species (ROS) or inducing the abnormal folding of proteins setting the conditions for the development of CNS degenerative diseases. The composition, size, and shape of nanoparticles, as well as the nature of their biocorona (protein corona), influence their toxicity, therefore it is required to identify which nanomaterials have a lower risk of inducing harmful reactions and how they are biodistributed once they enter the organism [12, 16].

In this regard, the specific factors that determine which nanoparticles enter the brain are mostly unknown. Size, shape, stiffness, and composition of nanoparticles are considered important and, under physiological conditions, the nature of the adsorbed biomolecule corona (proteins, lipids, etc.) determines the biological responses.
