Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

Viviana Marzaioli,¹ Juan Antonio Aguilar-Pimente,^1,2 Ingrid Weichenmeier,¹ Georg Luxenhofer,³ Martin Wiemann,⁴ Robert Landsiedel,⁵ Wendel Wohlleben,⁵ Stefanie Eiden,⁶ Martin Mempel,⁷ Heidrun Behrendt,¹ Carsten Schmidt-Weber,¹ Jan Gutermuth,^1,8 Francesca Alessandrini<sup>1

1</sup>Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany; ²Department of Dermatology and Allergy Biederstein, Technische Universität München (TUM) and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany, ³Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany; ⁴IBE R&D gGmbH, Münster, Germany; ⁵BASF, Ludwigshafen, Germany; ⁶Bayer Technology Services, Leverkusen, Germany; ⁷Department of Dermatology, Venereology and Allergology, Universitätsmedizin Göttingen (UMG), Göttingen, Germany; ⁸Department of Dermatology, Vrije Universiteit Brussel, Brussels, Belgium

Background: Silica (SiO₂) nanoparticles (NPs) are widely used in diverse industrial and biomedical applications. Their applicability depends on surface modifications, which can limit potential health problems.
Objective: To assess the potential impact of SiO₂ NP exposure and NPs chemical modifications in allergic airway inflammation.
Methods: Mice were sensitized by five repetitive intraperitoneal injections of ovalbumin/aluminum hydroxide (1 µg) over 42 days, then intratracheally instilled with plain or modified SiO₂ NPs (50 µg/mouse), and subsequently aerosol challenged for 20 minutes with ovalbumin. One or 5 days later, allergic inflammation was evaluated by cell differentiation of bronchoalveolar lavage fluid, lung function and gene expression and histopathology, as well as electron and confocal microscopy of pulmonary tissue.
Results: Plain SiO₂ NPs induced proinflammatory and immunomodulatory effects in vivo, highlighted by enhanced infiltration of inflammatory cells in the bronchoalveolar lavage fluid, induction of a pulmonary T helper type 2 (Th2) cytokine pattern, differentiation of type 2 macrophages, and by morphological changes in the lung of sensitized mice. These effects were dramatically attenuated using surface-functionalized NPs with amino and phosphate groups, but not with polyethylene glycol. The role of macrophages in taking up SiO₂ NPs was confirmed by flow cytometry, confocal microscopy, and gene expression analysis.
Conclusion: Our data suggest that amino and phosphate surface modifications, but not polyethylene glycol (PEG), mitigate the proinflammatory and immunomodulatory effect of SiO₂ NPs in allergic airway inflammation, paving the way for new strategies in the production of nanomaterials with lower health impact for humans.

Keywords: immunomodulation, allergic inflammation, health impact

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