Keywords: nanoparticles, cytotoxicity, lipid peroxidation, silica, safe-by-design
Summary:Silica (SiO2) nanoparticles are produced for a variety of applications and the amorphous form of silica is accepted as safe for use in food products by the US Food and Drug Administration. However, experimental studies in recent years have raised concerns regarding certain SiO2 nanoparticles (Shi et al. ACS Nano. 2012;6(3):1925-38; Zhang et al., J Am Chem Soc. 2012;134(38):15790-804). In the present study, we investigated a panel of SiO2 nanoparticles of different sizes (7 to 100 nm) and with different surface modifications using the human THP-1 and BEAS-2B cell lines and we found that the ultrasmall nanoparticles displayed the strongest cytotoxic effect. Surface modification with ethoxy-silane completely diminished the cytotoxicity of the SiO2 particles. Further analysis of the mechanism of cytotoxicity of the ultrasmall nanoparticles demonstrated that the mode of cell death was distinct from apoptosis, necroptosis, and ferroptosis. Cell-free electron paramagnetic resonance (EPR) spectroscopy experiments revealed the formation of hydroxyl radicals produced by surface-catalyzed decomposition of H2O2 and lipid peroxidation was shown to be a key feature in SiO2 nanoparticle-triggered cell death. These studies suggest that surface modification of SiO2 nanoparticles with ethoxy-silane may be considered as a feasible safe-by-design approach. This work was supported by the Swedish MISTRA Environmental Nanosafety Project.