Intrinsic and Extrinsic Properties Affecting Innate Immune Responses to Nanoparticles: The Case of Cerium Oxide

Abstract

We review the apparent discrepancies between studies that report anti-inflammatory effects of cerium oxide nanoparticles (CeO₂ NPs) through their reactive oxygen species-chelating properties and immunological studies highlighting their toxicity. We observe that several underappreciated parameters, such as aggregation size and degree of impurity, are critical determinants that need to be carefully addressed to better understand the NP biological effects in order to unleash their potential clinical benefits. This is because NPs can evolve toward different states, depending on the environment where they have been dispersed and how they have been dispersed. As a consequence, final characteristics of NPs can be very different from what was initially designed and produced in the laboratory. Thus, aggregation, corrosion, and interaction with extracellular matrix proteins critically modify NP features and fate. These modifications depend to a large extent on the characteristics of the biological media in which the NPs are dispersed. As a consequence, when reviewing the scientific literature, it seems that the aggregation state of NPs, which depends on the characteristics of the dispersing media, may be more significant than the composition or original size of the NPs. In this work, we focus on CeO₂ NPs, which are reported sometimes to be protective and anti-inflammatory, and sometimes toxic and pro-inflammatory.

Keywords: antioxidant activity; cerium oxide; immune response; inflammation; ion leaching; nanoparticle agglomeration; nanoparticle evolution; nanoparticles.

Figure 1

Different aspect and stability of commercial and designed CeO₂ nanoparticles (NPs). Different morphologies and sedimentation behavior of CeO₂ nanopowders (commercial, nominal size <25 nm) and CeO₂ NPs synthesized in the laboratory after dispersion in TMAOH 1 mM, a good stabilizer of metal oxide NPs. (A,B) Representative TEM images CeO₂ NPs and CeO₂ nanopowders, respectively (scale bar = 100 nm); (C) UV-VIS spectroscopy measurements over time of both samples after resuspension in TMAOH 1 mM and at the same NP concentration.

Figure 2

(A) Intrinsic and extrinsic properties of nanoparticles (NPs). Different properties of the NP, related to the NP itself (intrinsic) or to the NP behavior in the exposure media (extrinsic). For instance, we can design CeO₂ NPs with specific sizes and shapes, but agglomeration in the exposure media leads to specific surfaces, concentrations, mobilities, etc., very different from the initially prepared NPs. As agglomerated NPs behave as a large particle, this makes the NP more immunogenic and affects the concentration of NPs in different parts of the body, where they are accumulated in organs of the MPS system. Importantly, for the (immuno)toxicity aspects, agglomerates of NPs are no longer on the nanometric regime of sizes and may have similar consequences as the incidental inorganic microparticles, extensively investigated during the last century: burning oil residues, silica from mining or asbestos have been found stacked in affected tissues, causing pathologies such as silicosis, asbestosis, and/or inflammatory reactions. Thus, in this example, even if CeO₂ NPs are not toxic (and therapeutically beneficial) by themselves, they may be risky because they could be a source of toxic aggregates. (B) Graphical representative sizes of key entities capable of generating immune response and different NP morphologies and NP aggregates.