Immunotoxicity of nanomaterials in health and disease: Current challenges and emerging approaches for identifying immune modifiers in susceptible populations

Abstract

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

Instance maps as an organising concept for complex experimental workflows as demonstrated for (nano)material safety research

“…At the material side, studies focused on silica (SiO2) nanomaterials in the size range of 50-100 nm (depending on the method used; TEM, NTA; DLS intensity or number distribution) with different surface modifications, which are reported to be immunologically active in different ways but overall are considered to be safe [46]. In some studies, the impact of material surface (nanotopography) and functional modifications on API binding (molecular initiating event according to the adverse outcome pathway (AOP) concept [47]) were investigated, while in others, the different steps involved in specific immune reaction mechanisms (key events for beneficial vs. adverse outcomes) were analysed. Figure 9 illustrates the comprehensive experimental workflow overarching several immunotoxicity studies highlighting the different routes chosen for these studies, starting with the synthesis, surface functionalisation, and physico-chemical characterisation of the nanomaterials, the bionano interaction studies, and the determination of different biological / immunological endpoints.…”

Seven types of phenolic acid and inhibitory activity for protein tyrosine phosphatase 1B (PTP1B) from the stem of Sandoricum koetjape

“…Another important method for determining product safety is immunotoxicity testing. Immunotoxicity testing is required not only for product safety evaluation but also for product market approval [29]. Two phenolic acids that may be immunotoxic are chlorogenic acid and ferulic acid.…”

The Art of Nanoimmunobiotechnomedicine in Stem Cells and Gene Editing

“…The changing environment, be it due to pollution, global warming, or altered microbiomes, could lead to the rise of new autoimmune conditions. Nanoparticles can be designed to modulate immune responses, delivering immunosuppressive agents or even reprogramming immune cells to reduce unwarranted attacks on the body's own tissues [131][132][133].…”