Rethinking Nanosafety: Harnessing Progress and Driving Innovation

Abstract

This Special Issue brings together the best thought leaders in the field of nanosafety to inform, guide and direct the current and future directions of nanosafety research for the betterment of human and environmental health. Nanotechnology has long been recognized as an enabling technology underpinning advances across all industrial, governmental and societal sectors, and as such, the need to ensure that these technologies and their applications are safe is paramount. Indeed, worldwide a significant fraction of the total investment in nanotechnology has been focused on safety aspects, considering occupational exposure and consumer safety as priority areas. Since nanomaterials operate on the same sizescale and speed as biology, and can harness the proteins and other biomolecules used in nature to provide cellular structure and function by binding them to their surfaces and utilizing them to effectively engage with cellular receptors, nanomaterials have unprecedented access to living systems, offering the potential to cross biological barriers, to target specific cells and to deliver cargo to specific organelles. Indeed, this is the promise of nanomedicine, although the precision with which we can produce and functionalize nanomaterials is not yet nearly as refined as that of nature's tightly regulated signaling systems. However, as we explore nanomaterials interactions with living systems, to map and quantify the changes at cellular, tissue, organism and population levels, we are learning an enormous amount about how biology functions, as well as how nanomaterials function. Thus, nanosafety, rather than being just a necessary aspect of nanomaterials development and application, and a cornerstone of regulation, is a flourishing, innovative and exciting area of research, leveraging developments in chemoinformatics, systems toxicology and small molecule chemistry, and mixing them up with advances in analytical approaches, to produce exciting innovations. Nanosafety researchers are pioneering the development of advanced cell and tissue models and pushing forward our understanding of adverse outcome pathways and how they can be developed and validated, thereby accelerating progress in the transition away from animal testing. The mechanistic understanding of nanomaterials impacts on living systems, derived from nanosafety research, is being used to drive innovation in areas ranging from personalized nanomedicine to precision nano-agriculture. We were absolutely overwhelmed by the inspirational response from the community to this Special Issue call – with well over 60 colleagues agreeing to submit papers to the Special Issue, and >50 received to date! Given the scale and very high quality of the response, we had to split the Special Issue into two parts – with the first set of 29 papers presented here and a second set of papers to follow in July 2020. Part 1 of “Rethinking Nanosafety” thus includes 7 Reviews, 6 Communications and 16 Full Papers from researchers working at over 50 institutes spanning 21 countries (Austria, Australia, Belgium, Canada, China, Cyprus, Denmark, Finland, Germany, Ireland, Pakistan, Netherlands, Singapore, South Korea, Sweden, UK, USA, France, Italy, Turkey, Qatar). Interestingly, 25 of the papers have co-authors from multiple institutes and countries. This fantastic geographical distribution of co-authors, representing all continents, illustrates the breadth and depth of integrative nanosafety research that cuts across borders and barriers, and its highly collaborative nature with knowledge being co-developed across regulatory regimes. It is also illustrative of the global push to ensure that the enormous promise of nanomaterials and nanotechnologies are delivered safely and sustainability across healthcare, energy capture, environmental remediation and more. This Special Issue on “Rethinking Nanosafety” covers a range of emerging topics within nanosafety, which itself spans from the design and synthesis of nanomaterials, through characterization of their behavior and transformations in a range of exposure-relevant biofluids, elucidation of mechanisms of uptake and impact, quantification of uptake and impact and application of systems biology and nanoinformatics approaches, including artificial intelligence and machine learning (Figure 1). Our advancing knowledge is already allowing the application of safe-by design approaches to design-out features linked to toxicity, and of read-across approaches for gap filling datasets. For example, Haiyuan Zhang demonstrates a safety-by-design synthesis of metal oxide nanoparticles based on regulation of the nanomaterials' energy edges (10.1002/smll.201907643). Georgia Melagraki developed a tool for processing transmission electron microscopy images to extract additional shape and size descriptors and utilized these computed descriptors to develop a read-across model for prediction of zeta potential based on a k-nearest neighbors approach (10.1002/smll.201906588). Implementation of such approaches for gap-filling of datasets will facilitate the advancement of predictive and in silico nanosafety assessment. Part of the complexity of nanosafety arises from the dynamic nature of nanomaterials, many of whose properties are context dependent or extrinsic, changing depending on the surrounding conditions and available biomolecules. A key biotransformation of nanomaterials is their acquisition of a biomolecule corona: Li Shang introduces fluorescence resonance energy transfer as a means to probe protein corona formation in situ on quantum dots (10.1002/smll.201907633) while Rawi Ramautar demonstrates a quantitative metabolomics approach to probe the metabolites that bind to nanomaterials, including their co-interaction with proteins from serum to form a complete corona (10.1002/smll.202000295). Data demonstrating the role of nano-bio interactions and exposure conditions in determining the environmental hazard potential of nano-photocatalysts is presented by Sijie Lin (10.1002/smll.201907690), while Robert Hurt demonstrates both chemical and colloidal dynamics of MnO2 nanosheets when dispersed in biological media appropriate for nanosafety assessment (10.1002/smll.202000303). Peng Zhang reviews the state of science in terms of nanomaterials (bio)transformation in soil–plant systems and the implications of these transformations for food safety and applications of nanomaterials in agriculture, an area which is also ripe for application of machine learning (10.1002/smll.202000705). Introducing the theme of exposure route and its role in determining nanomaterials fate and toxicity, Chunying Chen reviews the contribution of the intestine in transforming nanomaterials and how this correlates with where and how the nanomaterials affect the intestine (10.1002/smll.201907665). The transformations of silver nanoparticles in a food matrix and gastro-intestinal fluids are evidenced by Arno Gutleb (10.1002/smll.201907687), and simulated digestion induced physicochemical transformations of size-sorted graphene oxide leading to altered toxicological outcomes in an in vitro model of the human intestinal epithelium are presented by Philip Demokritou (10.1002/smll.201907640). Gretchen Mahler demonstrates that TiO2 nanoparticles and commensal bacteria alter the mucus layer thickness and composition in a gastrointestinal tract model (10.1002/smll.202000601) and Jonathan Powell presents a murine oral-exposure model for nano and micro particulates and demonstrates that it has human relevance using food-grade TiO2 nanoparticles (10.1002/smll.202000486). The role of the liver as the dustbin of the body is well known, and it is the site of accumulation of all toxicants, with nanomaterials being no exception. Han Kiat Ho's Review of metal nanoparticles suggests that “all roads lead” to the liver and explores the implications of this for liver health (10.1002/smll.202000153). This is complemented by three experimental papers using liver cells and precision cut liver slices: Korin Wheeler demonstrates that surface chemistry of silver at low dose induced temporal effects on gene expression in human liver cells (10.1002/smll.202000299), while Tian Xia demonstrates mechanistic differences in cell death responses of Kupffer cells and hepatocytes to metal oxide nanomaterials (10.1002/smll.202000528) and Anna Salvati provides quantitative time-resolved data on the nanoparticle uptake, distribution and impact in precision-cut liver slices which are an important step towards bridging in vitro in vivo approaches (10.1002/smll.201906523). Given the well-established link between inhalation of particles and cardiovascular disease, Ulla Vogel's Review of the acute phase response as a biological mechanism-of-action of (nano)particle-induced cardiovascular disease is topical and timely providing new insights and potentially the first hint of a new adverse outcome pathway for nanomaterials (10.1002/smll.201907476). Two complementary Reviews of nanomaterials induced immunotoxicity provide important new insights. Albert Duschl asks the question of when would immunologists consider a nanomaterial to be safe? And provides recommendations for planning studies on nanosafety (10.1002/smll.201907483) while Diana Boraschi considers how to assess and conceptualize nanomaterial immunosafety by evaluating innate immunity across living species (10.1002/smll.202000598). A series of mechanistic papers utilizing a range of state-of-the-art approaches are also included. For example, Chor Yong Tay demonstrates that inflammation increases susceptibility of human small airway epithelial cells to pneumonic nanotoxicity (10.1002/smll.202000963) which may be of particular relevance given the current Covid-19 pandemic which leads to pneumonia in severe cases or immunocompromised individuals. Tae-Hyun Yoon uses mass cytometry and single-cell RNA-seq profiling to demonstrate the heterogeneity in human peripheral blood mononuclear cells interacting with silver nanoparticles (10.1002/smll.201907674) – this has particular relevance as understanding why some cells within a population are more susceptible to nanoparticle uptake may shed important light on so-called off-target effects for nanomedicines. Lucia Delogu demonstrates the use of single-cell mass cytometry (cytometry by time-of flight, CyTOF) to track the uptake of graphene oxide (GO) functionalized with AgInS2 nanocrystals (GO–In), using the indium (115In) channel to quantify the graphene uptake by individual monocytes and B cells, offering a new approach that can be translated to other 2D emerging materials and other cell types. Dario Greco shows that carbon nanomaterials promote M1/M2 macrophage activation (10.1002/smll.201907609) while Bengt Fadeel uses next-generation sequencing to reveals differential responses to acute versus long-term exposures to graphene oxide in human lung cells (10.1002/smll.201907686). Non-human species are also addressed well: Monika Mortimer shows that physical properties of carbon nanomaterials and nanoceria affect pathways important to the nodulation competitiveness of the symbiotic N2-fixing bacterium Bradyrhizobiu (10.1002/smll.201906055), while Pu-Chun Ke shows a positive effect from nanosilver which mitigates biofilm formation via inhibition of FapC amyloidosis (10.1002/smll.201906674). Also using silver nanomaterials with a range of different surface coatings and functionalizations, Iseult Lynch demonstrates multigenerational effects included accelerated ageing from exposures of Daphnia magna to silver nanomaterials, which are mitigated by ageing of the nanomaterials (10.1002/smll.202000301). Zhiyong Zhang shows that ceria nanoparticles and CeCl3 impact plant growth, biological and physiological parameters and nutritional value of soil grown common bean Phaseolus vulgaris (10.1002/smll.201907435). Part 1 of the Special Issue on “Rethinking Nanosafety” is rounded out by two additional Reviews: the first, a Review by Sijin Liu and Tian Xia who suggest that continued efforts on nano-EHS are critical to maintain sustainable growth of nano-industry worldwide. Their recommendations include accelerated application of 21st century toxicological approaches to nanosaferty, including use of libraries of standard nanomaterials, data analysis and modeling and predictive toxicology, and continued discovery on the mechanism of toxicity and AOPs using multiomics approaches. While much has already been discovered, the beauty of nanosafety research is that each partially answered question throws up several more questions to explore, usually demanding new experimental and computational models and technological advances! We would like to take this opportunity to thank all the authors and contributors to Part 1 of this Special Issue which truly captures the breath of nanosafety research and its pioneering and innovation-focused approach to understanding both the impact of nanomaterials on living systems and the impact of living systems on the nanomaterials themselves, and the dynamic and evolving interplay between the two. We are confident that the advances, insights and recommendations included herein will captivate and inspire the imagination of nanomaterials and nanosafety researchers across the globe. We also express our sincere thanks to the editorial team of Small, especially Dr. Ulf Scheffler and Dr. Amanda Mickley-Gass, for their untiring support. This Special Issue would not have been possible without their extended support. Importantly, this is Part 1 of a 2-part Special Issue, so please stay tuned for another set of exciting articles continuing to expand the horizons of nanosafety research coming in July 2020. Chunying Chen is a principal investigator at the Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety in the National Center for Nanoscience and Technology of China. Prof. Chen was one of the earliest researchers worldwide studying nanosafety, and has made key contributions toward a systematic understanding of the toxicology and safety of nanomaterials, and her pioneering contributions to understanding of the nano-bio interface and the fate of nanomaterials in biota have provided fundamental insights for the rational design of precision nanomedicine. David T. Leong is an associate professor of chemical and biomolecular engineering at the National University of Singapore. His research aims to discover novel nano-biology and to use this knowledge to develop nanoparticle specific rules that drive certain cellular effects and enable design of better (safer) nanomaterials. He also investigates the nanotoxicology of common and uncommon nanomaterials using a variety of cell lines to represent the various major tissues/organs of the body from the mouth to the gut, from the lungs to the kidneys and blood vessels, in both 2D and 3D culture systems. Iseult Lynch is Chair of Environmental Nanosciences at the School of Geography, Earth and Environmental Sciences, University of Birmingham. She has been at the forefront of nanosafety research for close to 15 years, having pioneered the concept of the nanomaterials protein (biomolecule) corona and, more recently, the environmental or “eco-corona.” Her research aims to understand the interface between engineered nanomaterials and the environment (abiotic and biotic components) and how this determines the nanomaterials' ultimate fate and behavior in organisms and the environment.

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