Nanomedicine (Epub ahead of print) ISSN 1743-5889 part of 10.2217/NNM.14.22 © 2014 Emanuele Papini Research Article Variations of the corona HDL:albumin ratio determine distinct effects of amorphous SiO 2 nanoparticles on monocytes and macrophages in serum Aim: We investigated monocyte and macrophage death and cytokine production induced by amorphous silica nanoparticles (SiO 2 -NPs) to clarify the role of defined serum corona proteins. Materials & methods: The cytotoxic proinflammatory effects of SiO 2 -NPs on human monocytes and macrophages were characterized in no serum, in fetal calf serum and in the presence of purified corona proteins. Results: In no serum and in fetal calf serum above approximately 75 μg/ml, SiO 2 - NPs lysed monocytes and macrophages by plasma membrane damage (necrosis). In fetal calf serum below approximately 75 μg/ml, SiO 2 -NPs triggered an endolysosomal acidification and caspase-1-dependent monocyte death (pyroptosis). The corona high-density lipoproteins:albumin ratio accounted for the features of the SiO 2 -NPs in serum. Discussion: Corona high-density lipoproteins are a major determinant of the differential cytotoxic action of SiO 2 -NPs on monocytes and macrophages. Original submitted 15 October 2013; Revised submitted 20 January 2014 KEYWORDS: amorphous silica nanoparticle • HDL • macrophage • monocyte • nanoparticle protein corona • pyroptosis In this study, we built on our previous observation that amorphous silica nano- particles (NPs; SiO 2 -NPs) kill human monocytes and macrophages at doses approximately ten-times lower than those required to affect epithelial cells or lymphocytes [1] . These cells internalize SiO 2 - NPs in acidic compartments much better than nonphagocytes, thus reaching an intracellular load more easily that results in catastrophic inflammatory death, characterized by lysis and release of proinflammatory cytokines, among which are TNF- a, IL-6 and IL-1b. Cell death and inflammation are relevant adverse reactions also to other NPs, and are hallmarks of many diseases, including cancer, silicosis and chronic inflammations. Pyroptosis, a programmed death occurring in myeloid cells characterized by lysis and by the secretion of powerful proinflammatory cytokines, is mediated by the cytosolic cysteine protease caspase-1 in inflammasomes [2,3] . Activated caspase-1 determines the conversion of inactive pro-IL-1b and pro-IL-18 into mature/active IL-1b/IL-18 and the processing of other ill-known intracellular proteins [4] , eventually inducing cell lysis. Among the microbial and tissue-derived factors that activate inflammasome-forming nucleotide- binding oligomerization domain (NOD)- like receptors [5,6] , micro- and nano-sized particulates are of particular pathological relevance. Cell-internalized particulates destabilize the phagolysosomal membrane, determining the cytosolic leak of cathepsin B, or related proteases, which in turn activate NLRP3 [3] . Since the lysosomotropic NH 3 and the vacuolar-type H + -ATPase (V-ATPase) inhibitor bafilomycin AI (BafAI) prevent NLRP3 activation induced by micro- or nano-particles in macrophages and dendritic cells [7–12] , the acidity of particle-entrapping endosomes (pH ~4.5–5) may play a role in mediating cellular effects [6] . Chiara Fedeli 1,2 , Daniela Segat 3,4 , Regina Tavano 1,2 , Giorgia De Franceschi 1 , Patrizia Polverino de Laureto 1 , Elisa Lubian 5 , Francesco Selvestrel 5 , Fabrizio Mancin ‡5 & Emanuele Papini ‡ * 1,2 1 Interdepartmental Research Center for Innovative Biotechnologies, Università di Padova, via U Bassi 58/B, I-35131, Padova, Italy 2 Department of Biomedical Sciences, Università di Padova, via U Bassi 58/B, I-35131, Padova, Italy 3 Department of Biology, Università di Padova, via U Bassi 58/B, I-35131, Padova, Italy 4 Institute for Rare Diseases ‘Mauro Baschirotto’, via Bartolomeo Bizio 1, 36023 Costozza di Longare (Vicenza), Italy (current address) 5 Department of Chemistry, Università di Padova, via Marzolo 1, I-35131, Padova, Italy *Author for correspondence: Tel.: +39 0498276301 Fax: +39 0498276159 emanuele.papini@unipd.it ‡ These authors contributed equally For reprint orders, please contact: reprints@futuremedicine.com