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The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount. The NanoSafety Cluster (NSC) delineates key safety and sustainability areas, pinpointing unresolved issues and research gaps to steer the development of safe(r) materials. Leveraging FAIR data management and integration, alongside the alignment of regulatory aspects, fosters informed decision-making and innovation. Integrating circularity and sustainability mandates clear guidance, ensuring responsible innovation at every stage. Collaboration among stakeholders, anticipation of regulatory demands, and a commitment to sustainability are pivotal for translating SSbD into tangible advancements. Harmonizing standards and test guidelines, along with regulatory preparedness through an exchange platform, is imperative for governance and market readiness. By adhering to these principles, the effective and sustainable deployment of innovative materials can be realized, propelling positive transformation and societal acceptance.

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The utility of decision-making tools for the risk governance of nanotechnology is at the core of this paper. Those working in nanotechnology risk management have been prolific in creating such tools, many derived from European FP7 and H2020-funded projects. What is less clear is how such tools might assist the overarching ambition of creating a fair system of risk governance. In this paper, we reflect upon the role that tools might and should play in any system of risk governance. With many tools designed for the risk governance of this emerging technology falling into disuse, this paper provides an overview of extant tools and addresses their potential shortcomings. We also posit the need for a data readiness tool. With the EUs NMP13 family of research consortia about to report to the Commission on ways forward in terms of risk governance of this domain, this is a timely intervention on an important element of any risk governance system.

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Nanosafety assessment has experienced an intense era of research during the past decades driven by a vivid interest of regulators, industry, and society. Toxicological assays based on in vitro cellular models have undergone an evolution from experimentation using nanoparticulate systems on singular epithelial cell models to employing advanced complex models more realistically mimicking the respective body barriers for analyzing their capacity to alter the immune state of exposed individuals. During this phase, a number of lessons were learned. We have thus arrived at a state where the next chapters have to be opened, pursuing the following objectives: (1) to elucidate underlying mechanisms, (2) to address effects on vulnerable groups, (3) to test material mixtures, and (4) to use realistic doses on (5) sophisticated models. Moreover, data reproducibility has become a significant demand. In this context, we studied the emerging concept of adverse outcome pathways (AOPs) from the perspective of immune activation and modulation resulting in pro-inflammatory versus tolerogenic responses. When considering the interaction of nanomaterials with biological systems, protein corona formation represents the relevant molecular initiating event (e.g., by potential alterations of nanomaterial-adsorbed proteins). Using this as an example, we illustrate how integrated experimental-computational workflows combining in vitro assays with in silico models aid in data enrichment and upon comprehensive ontology-annotated (meta)data upload to online repositories assure FAIRness (Findability, Accessibility, Interoperability, Reusability). Such digital twinning may, in future, assist in early-stage decision-making during therapeutic development, and hence, promote safe-by-design innovation in nanomedicine. Moreover, it may, in combination with in silico-based exposure-relevant dose-finding, serve for risk monitoring in particularly loaded areas, for example, workplaces, taking into account pre-existing health conditions. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

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The incidence of severe COVID-19 in children is low, and underlying mechanisms for lower SARS-CoV-2 susceptibility and self-limiting disease severity are poorly understood. Severe clinical manifestations in adults require SARS-CoV-2 inoculation in the lower respiratory tract, establishing a pulmonary disease phase. This may be either accomplished by direct inoculation of the thoracic region upon exposure to virion-laden aerosols, or by infection of the upper respiratory system and aspiration of virion-laden aerosols originating right there into the lower respiratory tract. The particularities of epithelial barriers as the anatomical site of first viral deposition specifically determine the initial characteristics of an innate immune response, emerging respiratory tissue damage and dysfunctionality, and hence, severity of clinical symptoms. We, thus, investigated by in silico modeling whether the combined effect of juvenile lung morphometry, children's ventilatory pattern and the peculiarities of the virion-laden aerosols' properties, render children more resilient to aerosol deposition in the lower respiratory tract. Our study presents evidence for major age-dependent differences of the regional virion-laden aerosol deposition. We identified deposition hotspots in the alveolar-interstitial region of the young adult. Our data reveal that children are void of corresponding hotspots. The inoculum quantum in the alveolar-interstitial region hotspots is found to be considerably related to age. Our results suggest that children are intrinsically protected against SARS-CoV-2 inoculation in the lower respiratory tract, which may help to explain the lower risk of severe clinical manifestations associated with a pulmonary phase.

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Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential to understand proteins' structural integrity at the material interface in order to develop safe-by-design nanovaccines. In this study, we utilized two model proteins, the wild-type allergen Bet v 1 and its hypoallergenic fold variant (BM4), to compare SiO2 nanoparticles with Alhydrogel® as particulate systems. A set of biophysical and functional assays including circular dichroism spectroscopy and proteolytic degradation was used to examine the antigens' structural integrity at the material interface. Conjugation of both biomolecules to the particulate systems decreased their proteolytic stability. However, we observed qualitative and quantitative differences in antigen processing concomitant with differences in their fold stability. These changes further led to an alteration in IgE epitope recognition. Here, we propose a toolbox of biophysical and functional in vitro assays for the suitability assessment of nanomaterials in the early stages of vaccine development. These tools will aid in safe-by-design innovations and allow fine-tuning the properties of nanoparticle candidates to shape a specific immune response.

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COVID-19, predominantly a mild disease, is associated with more severe clinical manifestation upon pulmonary involvement. Virion-laden aerosols and droplets target different anatomical sites for deposition. Compared to droplets, aerosols more readily advance into the peripheral lung. We performed in silico modeling to confirm the secondary pulmonary lobules as the primary site of disease initiation. By taking different anatomical aerosol origins into consideration and reflecting aerosols from exhalation maneuvers breathing and vocalization, the physicochemical properties of generated respiratory aerosol particles were defined upon conversion to droplet nuclei by evaporation at ambient air. To provide detailed, spatially-resolved information on particle deposition in the thoracic region of the lung, a top-down refinement approach was employed. Our study presents evidence for hot spots of aerosol deposition in lung generations beyond the terminal bronchiole, with a maximum in the secondary pulmonary lobules and a high preference to the lower lobes of both lungs. In vivo, initial chest CT anomalies, the ground glass opacities, resulting from partial alveolar filling and interstitial thickening in the secondary pulmonary lobules, are likewise localized in these lung generations, with the highest frequency in both lower lobes and in the early stage of disease. Hence, our results suggest a disease initiation right there upon inhalation of virion-laden respiratory aerosols, linking the aerosol transmission route to pathogenesis associated with higher disease burden and identifying aerosol transmission as a new independent risk factor for developing a pulmonary phase with a severe outcome.

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The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate matter, i.e., engineered nanoparticles. Nanoparticles are not inherently pathogenic, and yet cases have been described in which specific nanoparticle types can either induce innate/inflammatory responses or modulate the activity of activated innate cells. Many of these studies rely upon activation by agonists of toll-like receptors, such as lipopolysaccharide or peptidoglycan, instead of the more realistic stimulation by whole live organisms. In this review we examine and discuss the effects of nanoparticles on innate immune cells activated by live bacteria. We focus in particular on how nanoparticles may interfere with bacterial processes in the context of innate activation, and confine our scope to the effects due to particles themselves, rather than to molecules adsorbed on the particle surface. Finally, we examine the long-lasting consequences of coexposure to nanoparticles and bacteria, in terms of potential microbiome alterations and innate immune memory, and address nanoparticle-based vaccine strategies against bacterial infection.

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The immune system is professional in recognizing and responding to non-self, including nanomaterials. Immune responses by professional and nonprofessional immune cells are thus nearly inevitable upon exposure of cells and organisms to such materials. The state of research into taking the immune system into account in nanosafety studies is reviewed and three aspects in which further improvements are desirable are identified: 1) Due to technical limitations, more stringent testing for endotoxin contamination should be made. 2) Since under overdose conditions immunity shows unphysiological responses, all doses used should be justified by being equivalent to tissue-delivered doses. 3) When markers of acute inflammation or cell stress are observed, functional assays are necessary to distinguish between homeostatic fluctuation and genuine defensive or tolerogenic responses. Since immune activation can also indicate that the immune system considers a stimulus to be harmless and induces tolerance, activation markers by themselves do not necessarily imply a danger to the body. Guidelines such as these are necessary to approach the point where specific nanomaterials are classified as safe based on reliable testing strategies.

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