Abstract
In this essay, we offer the opinion that engineered nanomaterials are, by definition, materials that can interact with biological systems at the nanoscale, and that this very fact underlies both the promise and the peril of this multifaceted class of materials. Furthermore, nanomaterials are cloaked in host-derived proteins, lipids, or other biomolecules as they enter into a living organism and this so-called bio-corona may impact on subsequent interactions with biological structures. We will explore some examples of nanoscale effects of engineered nanomaterials, and discuss how such interactions may underpin toxicity, and, conversely, how nanoscale interactions may be harnessed for clinical applications, including the use of nanoparticles as drugs per se.
Life is a nanoscale phenomenon
In their seminal paper published one decade ago, Donaldson et al. (1) proposed that a new subcategory of toxicology – namely nanotoxicology – be defined to specifically address “the special problems likely to be caused by nanoparticles”, and the authors suggested that nanotoxicology be considered “a new frontier in particle toxicology”. However, one may argue, instead, that nanotoxicology represents a departure from the traditional toxicology of fine and ultrafine particles and fibers. In fact, nanotoxicology may be understood in light of “the interference of engineered nanomaterials with the functions of cellular and extracellular nanomachineries” (2). This view places emphasis on the fact that life (biology) is “a nanoscale phenomenon” (3). Indeed, living organisms are host to a range of dedicated intra- and extracellular nanoscale machines (4) and this, therefore, suggests that specific, size-dependent toxicities may ensue as a result of exposure to engineered nanomaterials. This does not, however, mean that all nanomaterials are inherently toxic (5), or that a nanospecific effect is necessarily detrimental to the host; in fact, the controlled manipulation of biological systems at the nanoscale may very well open up for novel therapeutic approaches. In this essay, we will explore both sides of the coin.
The right size in nanotoxicology
In his review on “the ‘right’ size in nanobiotechnology”, Whitesides argued that “small” – both nano and micro – must be a part of the future of biotechnology; which size is most important depends on what question one is asking (6). Surprisingly, in the field of nanotoxicology, the question of size, and more specifically, how one should define a nanomaterial (indeed, whether or not one should define nanomaterials in the first place) remains a matter of debate. Hence, while some have argued that we should not define nanomaterials, or to be more precise, that a ‘one-size-fits-all’ definition of nanomaterials will fail to capture what is important for addressing risk (7), others have stated that a definition of nanomaterials for regulatory purposes is urgently needed (8). As implied in the previous section, an operational “definition” of nanomaterials from a biological perspective would take into consideration whether or not nanomaterials impact on biological nanoscale machineries, be it inside or outside the cell.
As pointed out in a recent review on molecular modeling and its role in “structural nanotoxicology”, while engineered nanomaterials and cellular nanomachineries co-inhabit the same nano-universe, making nanoscale interactions possible, “it is the compatibility of physico-chemical properties of nanosurfaces with those of biological objects that define the driving forces, specificity, consequences and outcomes of their interactions” (9). Indeed, while we tend to grow cells in plastic dishes in the laboratory, in real life, many cells are adherent to extracellular matrices (ECM), which have a complex 3-D topography in the micrometer to nanometer range, and several studies have confirmed that surfaces with nanotopographies can influence cell behavior. In fact, some studies have suggested that stem cells are more responsive to topography than mature cell types and that they are actively seeking cues from their environment. Chen et al. (10) provided an excellent overview of the mechanotransduction mechanisms that potentially may underlie stem cell sensitivity to extracellular nanotopographies. In an interesting study, Conway et al. (11) demonstrated the design of potent multivalent conjugates that can control neural stem cell behavior. Hence, the ectodomain of ephrin-B2, normally an integral membrane protein ligand, was conjugated to a soluble biopolymer (hyaluronic acid) to yield multivalent nanoscale conjugates that induced signaling in neural stem cells and promoted their neuronal differentiation in vitro and in vivo. In another nanotechnological twist on the same topic, Shaw et al. (12) designed DNA origami nanostructures modified with ligands at well-defined positions and showed that the nanoscale spacing of ephrin-A5 controls membrane receptor activation in breast cancer cells and regulates their invasive behavior. Thus, it is clear that cells are not unacquainted with “nano”; in fact, cells in our body are capable of ‘sensing’ and responding to nanostructured surfaces. However, as we turn our attention from nanostructured surfaces to nanosized particles and “fibers” (nanotubes, nanowires), we need to address the question whether there are any “special problems” or nanospecific effects; in other words, is there any specific threshold in size below which novel or unanticipated effects occur? Or is there merely a gradual accentuation of the hazard in relation to the surface area of the particle? As pointed out by other investigators, it is evident that nanoparticles will display effects orders of magnitude greater than that of bulk materials at the same mass dose, due to the vastly greater surface area (13, 14). Auffan et al. (15) argued that evidence for “novel size-dependent properties”, rather than particle size, should be the primary criterion in any definition of nanoparticles in relation to their environmental health and safety. The question is: are there any novel properties, giving rise to nanospecific toxicities? Maynard (16) recently suggested that novelty may be overrated, and that the emphasis on novel features – either advantageous or deleterious – will “end up obscuring some risks, while overplaying others”. Indeed, not all nanoparticles are intrinsically hazardous (5), while, on the other hand, some are most likely very harmful, if exposure were to occur (17). Maynard also pointed out that “once in the body, the mechanisms by which these materials may cause harm will be predicated on the hard reality of material-biology interactions, and not on an arbitrary determination of novelty” (16). Indeed, the body may not care at all about “novel” material properties; what matters is whether or not engineered nanomaterials interfere with “the functions of cellular and extracellular nanomachineries” (2). In the following section, we provide a few examples of the hard reality of nanomaterial perturbations of intra- or extracellular biological structures. This is not intended as an exhaustive or representative account of the nanotoxicological literature. Moreover, we do not dispute that there are many publications supporting the view that established toxicological paradigms also are valid for nanomaterials, not least when it comes to nanomaterials with “fiber-like” dimensions, including certain carbon nanotubes (CNTs) [see (18) for a review]. Nonetheless, with this idiosyncratic sampling of the literature, we aim to highlight that size-dependent toxicities of nanomaterials do exist.
Towards a molecular nanotoxicology
Arguably, many nanotoxicological studies are not designed to evaluate the potential human health or environmental risk of nanomaterials using “realistic” concentrations of nanomaterials, but are aimed instead at elucidating potential mechanisms of cytotoxicity of the materials (19). Or, nanomaterials are in focus precisely because they are cytotoxic, which may be potentially useful, for instance, in cancer treatment. Here, we will discuss computational and experimental evidence suggesting nanospecific, i.e., size-dependent effects of nanomaterials, including CNTs, as well as metal and metal oxide nanoparticles. The translation of these effects into relevant hazards for human health or the environment will of course require further investigation.
Tsoli et al. (20) found that so-called Au55 clusters display cytotoxicity which seemed to be caused by the unusually strong interaction between the 1.4 nm particles and the major grooves of DNA, a biological nanostructure designed for genetic information storage. Only marginally smaller or larger particles showed drastically reduced toxicity, whereas significantly larger gold nanoparticles were completely non-toxic. Interestingly, among eleven different cancer and normal human cell lines, the metastatic melanoma cell lines, MV3 and BLM showed the most significant sensitivity to Au55. Notably, the effective concentration to reduce the cell number by 50% was approximately 180 times lower for the Au55 clusters than for the known anti-cancer drug, cisplatin for the BLM melanoma cells and over 200 times lower for the MV3 cell line (20).
In a more recent study, ultrasmall gold nanoparticles were shown to irreversibly block hERG channels in patch-clamp recordings (21). hERG forms the alpha subunit of one of the ion channel proteins that conducts potassium (K+) ions in the heart. The authors concluded that “the nanoparticles can act as an antagonist for a subcellular functional system due to shape complementarity at a molecular scale”. However, when the path-clamp recordings were performed in the presence of fetal calf serum, no blocking of the hERG channel was observed, most likely due to the formation of a shielding corona around the nanoparticles, which inhibited the direct interaction of the gold nanoparticles with the ion channel. Furthermore, the nanoparticles did not trigger cardiac arrhythmias in mice, suggesting no antagonistic effects of the particles in vivo (21).
Park et al. (22) demonstrated that carbon-based nanomaterials including single-walled CNTs (SWCNTs) with a diameter of 0.8–0.9 nm blocked K+ channel subunits in a dose-dependent manner. SWCNTs as well as C60 fullerenes were thus shown to interact with a variety of K+ channels expressed in mammalian (CHO) cells including hERG. Blockage was dependent on the shape and dimensions of the nanoparticles used and did not require any electrochemical interaction. SWCNTs were more effective than the spherical fullerenes and, for both, diameter was the determining factor. Based on electrophysiological experiments and docking, Park et al. found that the nanotubes presumably hampered channel function by fitting into the pore and thus either hindering ion movement or, alternatively, preventing further conformational steps (22). Similarly, fullerenes, with a diameter of 0.7 nm, were postulated to fit into the entrance of the channel and act as a “cork in a bottle” to stop ion permeation.
Further to this point, using large-scale molecular dynamics (MD) simulations, Zuo et al. (23) proposed that short SWCNTs can plug into the hydrophobic core of proteins to form stable complexes. This plugging of nanotubes disrupted and blocked the active sites of WW domains from binding to the corresponding ligands, presumably leading to the loss of function of the proteins. WW domains are important signaling and regulatory domains acting as functional modules for binding of specific protein ligands. The authors ascertained that “it is the small size of the SWCNT that makes its insertion into the hydrophobic core of a protein feasible, which results in the complete disruption of the active sites” (23). However, it should be noted that carboxylated SWCNTs can be degraded by proteins (peroxidases) in immune-competent cells including neutrophils and eosinophils and that this is suggested to occur through the interaction of the nanotubes with the active site of the enzyme (24, 25), implying that all CNT-protein interactions are not a priori deleterious (for the protein).
In a key study, C60 fullerenes were shown to act as specific signaling “mimics” (26). Hence, fullerenes were shown to interact with and modulate the function of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), a multimeric intracellular serine/threonine kinase central to Ca2+ signal transduction, in a manner similar to the well-documented interaction between the NMDA (N-methyl-D-aspartate) receptor subunit NR2B protein and CaMKII (26). The results from this detailed experimental study thus suggested that an inorganic nanoparticle can act like a cellular signaling protein and underscored the importance of specific interactions between nanoparticles and proteins. Indeed, the ability of C60 fullerenes to sustain the autonomous kinase activity of CaMKII may have significant implications for both the safety and for potential therapeutic applications of fullerenes, and further studies are warranted. Moreover, a recent in vitro study revealed that several types of metal oxide nanoparticles adsorbed to the various subunits of the proteasome and that the nanoparticles modulated the function of the proteasome in a manner dependent on their size and surface charge (and dose) (27). The ubiquitin-proteasome system is responsible for the controlled degradation of the majority of proteins in the cell, thereby regulating most cellular processes. It will therefore be important to determine whether or not nanoparticles could inhibit or promote proteasome activity in living cells.
Sargent et al. (28) provided evidence of SWCNT interference with the mitotic spindle in human airway epithelial cells leading to induction of aneuploidy, an early event in the progression of many cancers. Notably, significant disruption of the mitotic spindle by SWCNTs was detected at occupationally relevant doses (29). The CNT bundles are similar to the size of microtubules that form the mitotic spindle and this “bio-mimicry” may explain how these nanomaterials are incorporated into the mitotic spindle apparatus.
In a recent computational study, the internal hydrophobic pockets of some Toll-like receptors (TLRs) were found to be capable of binding SWCNTs and fullerenes (30). TLRs are receptors that bind structurally conserved motifs expressed by various microorganisms and they are expressed by sentinel cells such as macrophages and epithelial cells. The latter findings suggest that carbon-based nanomaterials could engage the same pathways as bacteria and viruses to trigger inflammation or other immune effects. One may ask whether this is an example of “mimicry” between carbon-based nanomaterials and microbes, or whether these cellular receptors have, in fact, evolved to handle different forms of nanoscale entities; mankind has been exposed to carbon-based particles long before the advent of nanotechnology. Nevertheless, these computational studies suggest a molecular mechanism for the inflammatory effects seen for carbon-based nanomaterials such as SWCNTs and this certainly warrants experimental verification. It is notable that graphene oxide (GO) has been shown to trigger TLR4-dependent cell death in macrophages (31) even though it was not determined whether this was via a direct interaction of GO with TLR4.
Nanomaterials may also interfere with extracellular biological structures as a function of their size. In a particularly illustrative study, Setyawati et al. (32) provided evidence that spherical TiO2 nanoparticles (23.5 nm) caused endothelial cell leakiness in an in vitro model using human microvascular endothelial cells. This was suggested to occur through the physical interaction between the nanoparticles and the adherens junction protein VE-cadherin. Adherens junctions are protein complexes that occur at cell-cell junctions in epithelial and endothelial tissues. As a result of this interaction, VE-cadherin was phosphorylated at intracellular residues and actin remodeling occurred within the cell, leading to cell retraction, and leakiness. The authors also showed that injections of TiO2 nanoparticles caused leakiness of subcutaneous blood vessels in mice (32). These findings suggest a novel non-receptor-mediated mechanism of toxicity by which nanomaterials migrate into and disrupt adherens junctions.
Thus, nanomaterials may, in fact, engage in specific molecular interactions with intra- or extracellular biological systems, meaning that size-dependent effects may come into play. However, coming back again to the question of novelty, one may argue that these nanoscale effects of engineered nanomaterials are not “novel” at all. Instead, the examples cited above serve to illustrate how man-made nanomaterials may engage or interfere with biological systems in an “ancient” manner, i.e., in a manner similar to endogenous ligands or exogenous biological entities (microorganisms). Indeed, several if not all of these examples may be viewed as instances of “bio-mimicry”.
The coronation of nanomaterials
One may ask whether the biological “mimicry” of certain nanomaterials is associated solely with the intrinsic features of the nanomaterials, such as size and shape, and/or whether these phenomena – exemplified in the previous section – are due to the acquisition of a bio-corona on the surface of the nanomaterials, affording a new biological ‘identity’ to the nanomaterial (33). Indeed, as discussed by Stauber and co-workers in a recent review, “by enshrouding the particle, the protein adsorption layer defines the nanoparticle surface and mediates further interactions between the nanoparticles and the biological environment” (34). Thus, when assessing interactions between nanomaterials and the (extracellular) biological environment, the corona of biomolecules should be taken into account. However, it remains to be understood whether the biomolecule-nanoparticle complex exists as a stable entity following cellular uptake: perhaps, under certain conditions, the corona is stripped off from the nanoparticle, thus revealing the true (intrinsic) ‘identity’ of the nanomaterial in question (35). The bio-corona concept has been discussed in detail in several excellent reviews (36, 37). Here, we shall consider a few illustrative bio-corona studies and the implications of such interactions for the molecular toxicology of engineered nanomaterials.
First, with respect to the “mimicry” of nanoparticles with biological entities, consider the fact that copolymer nanoparticles immersed in human plasma were shown to display lipid and protein binding patterns that correspond closely with the composition of high-density lipoprotein (HDL) (38). This means that such nanoparticles, enveloped in the body’s own proteins and lipids, may be “seen” by living systems as HDL complexes. This, therefore, could potentially underlie nanoparticle toxicities, but also opens up for novel delivery strategies by exploiting the natural transport pathways of HDL particles. The latter study stands out as one of the few studies on the lipid corona; until now, the literature has been biased towards the study of the plasma protein corona. However, it is certainly important to consider other biomolecules apart from proteins, as well as other biological compartments apart from the bloodstream. To illustrate this point, Li et al. (39) explored the interaction of 12 types of nanoparticles with DNA. The authors found that nanoparticles with a high affinity for DNA strongly inhibited DNA replication, whereas nanoparticles with low affinity had no or minimal effects. Of course, in real life, beyond the test tube, one may need to take into account the combined effects of different classes of adsorbed biomolecules (proteins, lipids, nucleic acids, carbohydrates), and potential interactions within the corona.
In this context, the recent work of Kelly et al. (40) is worth noting. Using transferrin-coated polystyrene nanoparticles as a model, the authors performed epitope mapping in order to clarify the presentation of functional molecular motifs (i.e., antibody binding epitopes) on the surface of the nanoparticles. This is important as this would presumably determine whether nanoparticles will engage specifically with cellular receptors via the adsorbed layer of proteins. It is also important to consider that the size and curvature (or, geometry) of the nanoparticle may play an active role in determining the degree of receptor crosslinking and subsequent cell responses, as shown in a previous study using gold nanoparticles coated with a monoclonal antibody that binds to ErbB2 receptors on breast cancer cells (41). In addition, the binding and unfolding of proteins on the surface of nanoparticles may reveal cryptic epitopes (i.e., epitopes that are normally buried and not seen by the immune system) which in turn may promote interaction with cellular receptors, as shown for fibrinogen on the surface of gold nanoparticles (42). Moreover, it remains possible that a protein layer on the surface of the nanoparticles may affect the agglomeration of the nanoparticles, which in turn could impact on cellular interactions. Indeed, Ehrenberg et al. (43) concluded, based on studies of a series of polystyrene nanoparticles that the capacity of nanoparticle surfaces to adsorb protein is indicative of their tendency to associate with cells, but they also concluded that “cellular association is not dependent on the identity of adsorbed proteins and therefore unlikely to require specific binding to any particular cellular receptors”. Simberg et al. (44) studied the protein corona on dextran-coated iron oxide nanoparticles and its implications for cellular uptake and found that both the dextran coat and the iron oxide core remained accessible to specific probes after incubation in plasma, suggesting that the nanoparticle surface could be available for recognition by macrophages, irrespective of the protein coating. Our recent studies have revealed that the plasma protein corona promotes uptake of silica-coated iron oxide nanoparticles by primary human macrophages, but does not facilitate cellular uptake of dextran-coated nanoparticles (45).
Finally, one may ask whether the bio-corona may confound the targeting of nanoparticles with specific ligands grafted onto their surface (46) or whether the surface functionality of nanoparticles can be preserved in the presence of a protein corona (47). Indeed, it remains possible that the protein corona could be exploited through the purposeful control of the bio-corona composition. Zhang et al. (48) have provided one elegant example whereby retinol-conjugated polyetherimine nanoparticles were shown to selectively recruit retinol binding protein 4 (RBP) in its corona, enabling targeted delivery of antisense oligonucleotides to hepatic stellate cells.
The other side of the coin: nanomedicine
With respect to nanomedicine, nanomaterials are generally viewed as potential carriers of (conventional) drugs. However, as pointed out by Yang et al. (49) in their recent review, nanomaterials could also possess intrinsic therapeutic properties and may be considered as drugs per se. In this context, nanoscale interactions between nanomaterials and biological receptors are of utmost importance. Here, we will highlight two classes of nanomaterials – dendrimers and metallofullerenols – which appear to have the potential to be used as macromolecular medicines or drugs per se.
Dendrimers are synthetic, “tree-like” (branched) polymers that can be prepared with structural precision, with defined molecular weight and a defined number of surface end-groups that have the potential to interact in a polyvalent manner with biological molecules [see (50) for an excellent introduction]. Studies conducted over the past decade have shown that these macromolecules can be used as immune-modulating drugs.
Shaunak et al. (51) demonstrated in a clinically relevant animal model that glucosamine-conjugated, anionic poly(amidoamine) dendrimers could be used safely and synergistically to prevent scar tissue formation. The dendrimer glucosamine conjugate inhibited TLR4-mediated lipopolysaccharide (LPS) induced synthesis of pro-inflammatory chemokines and cytokines in macrophages and dendritic cells while the dendrimer glucosamine 6-sulfate conjugate blocked endothelial cell proliferation and angiogenesis (blood vessel formation). When dendrimer glucosamine and dendrimer glucosamine 6-sulfate were used in combination in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery (of the eye), they increased the long-term success of the surgery from 30% to 80% (51). Some 5 years later, Chauhan et al. (52) discovered “unexpected” anti-inflammatory properties for naked, unmodified poly(amidoamine) dendrimers in several different in vitro and in vivo assays, and found that these effects manifested in a manner dependent on the nature of the dendrimer surface functionality, the dendrimer generation level, and on time elapsed after administration. The authors concluded that “this strongly suggests that nanoscale size may be mediating this biological response” (52). In a more recent study, Hayder et al. (53) provided evidence for the therapeutic potential of azabisphosphonate (ABP)-capped dendrimers in the treatment of an inflammatory disease, rheumatoid arthritis (RA). Using mouse models of autoimmune arthritis, the authors showed that dendrimer ABP targets monocytes, leading to a decrease in the production of pro-inflammatory cytokines, an increase in the production of anti-inflammatory cytokines, and inhibition of osteoclast differentiation. Comparable biological activity was also demonstrated ex vivo in human synovial tissue. In conclusion, dendrimer ABP might represent a new drug candidate for combating the inflammatory and bone-eroding features of RA (53).
Teo et al. sought to develop a non-antibiotic approach to prevent acute gut wall damage in infectious diarrhoeas (54). Molecular modelling studies suggested that the glycosylated surface of dendrimers confers physico-chemical properties that enable electrostatic interactions with lymphocyte antigen 96 or MD2 in the TLR4-MD2-LPS complex (55). The LPS-TLR4 interaction is regarded as the key interaction between Gram-negative bacteria and the innate immune system. The authors then showed that a poly(amidoamine) dendrimer glucosamine reduced the induction of IL-6 by Gram-negative bacteria. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In a rabbit model of shigellosis, PETIM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion (54). The authors suggested that orally delivered dendrimer molecules could be useful for preventing gut wall tissue damage in a wide spectrum of diseases.
The metallofullerenol nanoparticles are fullerene derivatives consisting of a metal atom inside a fullerene cage and are currently investigated for their unique mechanical, thermal and electrochemical properties. In particular, Gadolinium (Gd) based metallofullerenes are developed as innovative contrast agents, and may also act as anti-cancer agents. Meng et al. (56) found that Gd@C82(OH)22 downregulated multiple angiogenic factors and in vivo studies using a MCF-7 human breast cancer xenograft model demonstrated that the metallofullerenol nanoparticles displayed anti-cancer efficacy comparable to the chemotherapeutic drug paclitaxel. In a subsequent study, the same nanoparticles were shown to inhibit cancer metastasis through matrix metalloproteinase (MMP) inhibition (57). Intriguingly, treatment with the nanoparticles induced a dense fibrous “cage” potentially “imprisoning” the cancer cells.
Kang et al. (58) showed that Gd@C82(OH)22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Moreover, using large-scale MD simulations, the authors could demonstrate that Gd@C82(OH)22 inhibits MMP-9 mainly via an exocite interaction, whereas the well-known catalytic site only plays a minimal role. This therefore provides a perfect example of a specific nanoscale interaction between a synthetic nanoparticle and a biological receptor (protein) that can be harnessed for therapeutic gain. More recently, Liu et al. (59) reported that Gd@C82(OH)22 are essentially non-toxic to normal mammary epithelial cells, while these nanoparticles possess intrinsic inhibitory activity against triple-negative breast cancer cells. Moreover, the authors provided evidence that the nanoparticles specially inhibited so-called breast cancer stem cells, resulting in the abrogation of tumor initiation and metastasis (59). They found that under hypoxic conditions in the tumor microenvironment, crucial surface modifications of the Gd-metallofullerenol occurred, which promoted tumor uptake, enhancing the elimination of cancer stem cells.
Taken together, these studies highlight that certain classes of nanomaterials can be exploited as drugs per se and not only as drug carriers (or, imaging agents). Hence, a detailed understanding of nanomaterial interactions with intra- or extracellular biological structures may not only instruct us on the potential toxicity of nanomaterials but could also inform the design of novel nanomedicines; there are two sides to the coin.
Concluding remarks
It has been argued that “passing into the nano-realm does not necessarily infer any new and specific properties; therefore the arbitrary assumption of different and ‘nano-specific’ toxicity appear[s] to be unfounded” (13). This is certainly a reasonable statement; indeed, one should not a priori assume that all nanomaterials, because they are small, would necessarily elicit “novel” toxicities, or any toxicity for that matter. However, as we have highlighted here, there are emerging examples of nanoscale interactions between nanomaterials and biological systems that warrant close attention. Indeed, cells can be viewed as miniaturized factories consisting of numerous nanoscale “machines” (4) and it is therefore of considerable interest and importance to understand whether engineered nanomaterials, by virtue of their nanoscale dimensions, could interfere specifically with such biological systems (60). We believe that the combination of experimental and computational studies will prove especially useful in elucidating these interactions. Naturally, careful material characterization remains of paramount importance, and should take into account the intrinsic or synthetic ‘identity’ as well as the biological “identity” of the nanomaterials (33).
About the authors
Audrey Gallud received her PhD in Nanomedicine from the University of Montpellier in France in 2014. She was then recruited to the Institute of Environmental Medicine, at Karolinska Institutet. Her current research is focused mainly on immunotoxicity of engineered nanomaterials and this work is conducted in the frame of the EU-funded project FP7-NANOSOLUTIONS which aims to achieve a systems biology understanding of nanomaterial interactions with biological systems at the molecular, cellular, and organism levels.
Bengt Fadeel is a Professor of Medical Inflammation Research at the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and Adjunct Professor of Environmental and Occupational Health, University of Pittsburgh. He is a Fellow of the Academy of Toxicological Sciences (ATS). He received his MD in 1997 and PhD in 1999 from Karolinska Institutet. Dr Fadeel is the past coordinator of FP7-NANOMMUNE, an EU-funded consortium focused on hazardous effects of nanomaterials on the immune system, and currently engaged in several other EU-funded nanosafety projects as well as the Flagship Project GRAPHENE, and member of the national MISTRA Environmental Nanosafety consortium.
Acknowledgments
The authors are supported, in part, by the Swedish Research Council and the European Commission (FP7-NANOSOLUTIONS, Grant Agreement No. 309329; and the Future Emerging Technologies (FET) project GRAPHENE, Grant Agreement No. 604391).
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