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General Nanotoxicity Mechanism

The use and investigation of nanomaterials for novel biomedical applications has been increasing rapidly in last few years. One may concern limited the usage of nanomaterials is their toxicology to the human body and environment. Some susceptible groups, such as diseased, neonate, pregnant, and aged populations, are more easily suffering from the exposure to nanomaterials due to their compromised immunity, reduced protection mechanism, and impaired self-repair ability. A variety of instinct properties of nanoparticles may affect their nanotoxicity, such as size, surface, shape, charges, functional groups, chemical composites, UV light activation, aggregation and dissolution, and their interaction with cells. The detailed mechanisms and effects cytotoxicity, genotoxicity, and immunotoxicity of nanoparticles have not yet been fully clear. But some general mechanisms are discussed below, such as the overproduction of ROS, inflammation, non-degradation or self-degradation, and change in cell morphology and cytoskeleton network. In order to use nanomaterials in a safe and well-controlled manner to benefit of mankind, long-term nanotoxicity studies are required, as well as optimizing properties of nanoparticles to reduce and even diminish the toxicity.

1. Overproduction of ROS

The generation of the reactive oxygen species (ROS) is considered to be the foremost mechanism of nanotoxicity. In general, most cell types can tolerate the small and transient increases of ROS. However, high levels or long time enhanced level of ROS will cause cell damage. When exposed to nanoparticles, cells will significantly overproduce ROS, resulting in the generation of oxidative stress. ROS can interact with cellular macromolecules including functional proteins and DNA, resulting in the signal transductions disruption and dysfunction. Therefore, these overproduce ROS-affected cells may fail to maintain their normal physiological functions, which lead to the unregulated cell signaling, change in cell motility, DNA damage, autophagy, apoptosis, necrosis, fibrosis, and carcinogenesis. The induction of ROS has also been frequently reported for a variety of nanoparticles, especially metal- and carbon- based nanoparticles. For example, quantum dots and carbon nanotubes have been frequently reported to show their nanotoxicity due to the induced ROS overproduction.

2. Inflammation-Mediated Nanotoxicity

Immune system is the first safeguard and self-defense mechanism of the human body to resist the potential toxicity of the infection, malignancy, and exogenous agents. The exposure to nanoparticles often causes some immune perturbation, for example, elevate or suppress the immune response. The immune toxicity of nanoparticles is also related to the ROS generation. Studies have shown that upon the exposure of nanoparticles, mitochondria can produce ROS and trigger the activation of inflammasomes in phagocytic cells. The phagocyte-derived ROS are also known to injure human tissues and to contribute to inflammatory response. Inflammation has been shown to be an important cause of toxicity and promote cell death. For example, the production of a variety of pro-inflammatory cytokines, such as TNF-a, IL-1, and IL-8, will end up with induced-apoptosis and autophagy. Some studies showed that the lipid-based nanoparticles can activate the complement cascade and lead to hypersensitivity reactions and anaphylaxis.

3. Nanoparticle Degradability

For nanoparticles, some of them can be degraded easily in the human body microenvironment while some other are non-degradable or slow degradable and will accumulate in the organs or cells leading to some unknown long-term toxic effect. One major concern is the potential interaction or interference of nanoparticles with various biological processes. The small size, high surface area, and high local charge densities can make nanoparticles easily interact with surrounding biological molecules. For example, the surface charges on nanoparticles can favor their binding of serum enzymes, leading to a so-called protein corona and affect enzymatic regulatory mechanisms.

For degradable nanoparticles, their intracellular toxic effect is also one of the important mechanisms. The destabilization of nanoparticle can lead to the release of toxic components and the change the microenvironment in the body. In general, nanoparticles can be internalized by cells via endocytic mechanisms. The pH values in endosomes (pH~6) and lysosomes (pH~4.5) are much lower than the extracellular environment (pH~7). The local pH change and the presence of degradative enzymes in the cells, such as cathepsin L, make some nanoparticles degradable and lose their coating on their surface. For example, studies have shown that some iron oxide nanoparticles are acid etching in the acidic environment of the endosomes and generate free ions, resulting in the decrease of the size, the loss of their magnetic function, and even effects on cell homeostasis. Quantum dots have also been found to be acid etching by the physiologically relevant concentrations of hydrogen peroxide and hypochlorous acid, which are the products of phagocytes.

4. Cell Morphology and Cytoskeleton Defects

Although the detailed mechanism is still unclear, nanoparticles with certain physical dimensions can alter the cellular morphology or affect the cellular functional components such as the cytoskeleton network, mitochondria, and synaptic machinery. It is a common sense that cell functions are based on the normal morphology and well-functional of all components. The cytoskeleton plays a significant role in cell shape, motility, division cells-extracellular matrix adhesive interaction, and neuronal architecture formation. The cytoskeletal deformations will decrease the capacity of cell functions. For example, silver particles have been shown to induce neurotoxicity by disrupting destruct tubulin and actin cytoskeletal proteins, dissolving synaptic proteins, and compromising mitochondria function.

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