Archives of Toxicology

, Volume 85, Issue 7, pp 733–741 | Cite as

Nanoparticles: molecular targets and cell signalling

  • Francelyne Marano
  • Salik Hussain
  • Fernando Rodrigues-Lima
  • Armelle Baeza-Squiban
  • Sonja Boland
Review Article


Increasing evidence linking nanoparticles (NPs) with different cellular outcomes necessitate an urgent need for the better understanding of cellular signalling pathways triggered by NPs. Oxidative stress has largely been reported to be implicated in NP-induced toxicity. It could activate a wide variety of cellular events such as cell cycle arrest, apoptosis, inflammation and induction of antioxidant enzymes. These responses occur after the activation of different cellular pathways. In this context, three groups of MAP kinase cascades [ERK (extracellular signal-regulated kinases), p38 mitogen-activated protein kinase and JNK (c-Jun N-terminal kinases)] as well as redox-sensitive transcription factors such as NFκB and Nrf-2 were specially investigated. The ability of NPs to interact with these signalling pathways could partially explain their cytotoxicity. The induction of apoptosis is also closely related to the modulation of signalling pathways induced by NPs. Newly emerged scientific areas of research are the studies on interactions between NPs and biological molecules in body fluids, cellular microenvironment, intracellular components or secreted cellular proteins such as cytokines, growth factors and enzymes and use of engineered NPs to target various signal transduction pathways in cancer therapy. Recently published data present the ability of NPs to interact with membrane receptors leading to a possible aggregation of these receptors. These interactions could lead to a sustained modulation of specific signalling in the target cells or paracrine and even “by-stander” effects of the neighbouring cells or tissues. However, oxidative stress is not sufficient to explain specific mechanisms which could be induced by NPs, and these new findings emphasize the need to revise the paradigm of oxidative stress to explain the effects of NPs.


Nanoparticle Oxidative stress Cell signalling Inflammation Nano–bio interactions Apoptosis 


  1. Archambault V, Glover DM (2009) Polo-like kinases: conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol 10:265–275PubMedCrossRefGoogle Scholar
  2. Auger F, Gendron MC, Chamot C, Marano F, Dazy AC (2006) Responses of well-differentiated nasal epithelial cells exposed to particles: role of the epithelium in airway inflammation. Toxicol Appl Pharmacol 215:285–294PubMedCrossRefGoogle Scholar
  3. Ayres JG, Borm P, Cassee FR, Castranova V, Donaldson K, Ghio A, Harrison RM, Hider R, Kelly F, Kooter IM, Marano F, Maynard RL, Mudway I, Nel A, Sioutas C, Smith S, Baeza-Squiban A, Cho A, Duggan S, Froines J (2008) Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential—a workshop report and consensus statement. Inhal Toxicol 20:75–99PubMedCrossRefGoogle Scholar
  4. Basu S, Harfouche R, Soni S, Chimote G, Mashelkar RA, Sengupta S (2009) Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy. Proc Natl Acad Sci U S A 106:7957–7961PubMedCrossRefGoogle Scholar
  5. Baulig A, Sourdeval M, Meyer M, Marano F, Baeza-Squiban A (2003) Biological effects of atmospheric particles on human bronchial epithelial cells. Comparison with diesel exhaust particles. Toxicol In Vitro 17:567–573PubMedCrossRefGoogle Scholar
  6. Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, Surprenant A, Lopez-Castejon G, Mann S, Davis SA, Hails LA, Ingham E, Verkade P, Lane J, Heesom K, Newson R, Case CP (2009) Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol 4:876–883PubMedCrossRefGoogle Scholar
  7. Blanchet S, Ramgolam K, Baulig A, Marano F, Baeza-Squiban A (2004) Fine particulate matter induces amphiregulin secretion by bronchial epithelial cells. Am J Respir Cell Mol Biol 30:421–427PubMedCrossRefGoogle Scholar
  8. Borm PJ, Muller-Schulte D (2006) Nanoparticles in drug delivery and environmental exposure: same size, same risks? Nanomed 1:235–249CrossRefGoogle Scholar
  9. Borm P, Klaessig FC, Landry TD, Moudgil B, Pauluhn J, Thomas K, Trottier R, Wood S (2006a) Research strategies for safety evaluation of nanomaterials, part V: role of dissolution in biological fate and effects of nanoscale particles. Toxicol Sci 90:23–32PubMedCrossRefGoogle Scholar
  10. Borm PJ, Robbins D, Haubold S, Kuhlbusch T, Fissan H, Donaldson K, Schins R, Stone V, Kreyling W, Lademann J, Krutmann J, Warheit D, Oberdorster E (2006b) The potential risks of nanomaterials: a review carried out for ECETOC. Part Fibre Toxicol 3:11PubMedCrossRefGoogle Scholar
  11. Brown DM, Wilson MR, MacNee W, Stone V, Donaldson K (2001) Size-dependent proinflammatory effects of ultrafine polystyrene particles: a role for surface area and oxidative stress in the enhanced activity of ultrafines. Toxicol Appl Pharmacol 175:191–199PubMedCrossRefGoogle Scholar
  12. Brown DM, Donaldson K, Borm PJ, Schins RP, Dehnhardt M, Gilmour P, Jimenez LA, Stone V (2004) Calcium and ROS-mediated activation of transcription factors and TNF-alpha cytokine gene expression in macrophages exposed to ultrafine particles. Am J Physiol Lung Cell Mol Physiol 286:L344–L353PubMedCrossRefGoogle Scholar
  13. Brunekreef B, Holgate ST (2002) Air pollution and health. Lancet 360:1233–1242PubMedCrossRefGoogle Scholar
  14. Cedervall T, Lynch I, Foy M, Berggard T, Donnelly SC, Cagney G, Linse S, Dawson KA (2007a) Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew Chem Int Ed Engl 46:5754–5756PubMedCrossRefGoogle Scholar
  15. Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, Dawson KA, Linse S (2007b) Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A 104:2050–2055PubMedCrossRefGoogle Scholar
  16. Dausend J, Musyanovych A, Dass M, Walther P, Schrezenmeier H, Landfester K, Mailander V (2008) Uptake mechanism of oppositely charged fluorescent nanoparticles in HeLa cells. Macromol Biosci 8:1135–1143PubMedCrossRefGoogle Scholar
  17. Dawson KA, Salvati A, Lynch I (2009) Nanotoxicology: nanoparticles reconstruct lipids. Nat Nanotechnol 4:84–85PubMedCrossRefGoogle Scholar
  18. Deng ZJ, Mortimer G, Schiller T, Musumeci A, Martin D, Minchin RF (2009) Differential plasma protein binding to metal oxide nanoparticles. Nanotechnology 20:455101PubMedCrossRefGoogle Scholar
  19. Ding M, Kisin ER, Zhao J, Bowman L, Lu Y, Jiang B, Leonard S, Vallyathan V, Castranova V, Murray AR, Fadeel B, Shvedova AA (2009) Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells. Toxicol Appl Pharmacol 241:260–268PubMedCrossRefGoogle Scholar
  20. Dobrovolskaia MA, McNeil SE (2007) Immunological properties of engineered nanomaterials. Nat Nanotechnol 2:469–478PubMedCrossRefGoogle Scholar
  21. Donaldson K, Stone V, Tran CL, Kreyling W, Borm PJ (2004) Nanotoxicology. Occup Environ Med 61(9):727–728PubMedCrossRefGoogle Scholar
  22. Donaldson K, Tran L, Jimenez LA, Duffin R, Newby DE, Mills N, MacNee W, Stone V (2005) Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure. Part Fibre Toxicol 2:10PubMedCrossRefGoogle Scholar
  23. Donaldson K, Borm PJ, Castranova V, Gulumian M (2009) The limits of testing particle-mediated oxidative stress in vitro in predicting diverse pathologies; relevance for testing of nanoparticles. Part Fibre Toxicol 6:13PubMedCrossRefGoogle Scholar
  24. Duffin R, Tran L, Brown D, Stone V, Donaldson K (2007) Proinflammogenic effects of low-toxicity and metal nanoparticles in vivo and in vitro: highlighting the role of particle surface area and surface reactivity. Inhal Toxicol 19:849–856PubMedCrossRefGoogle Scholar
  25. Eom HJ, Choi J (2009) Oxidative stress of CeO2 nanoparticles via p38-Nrf-2 signaling pathway in human bronchial epithelial cell, Beas-2B. Toxicol Lett 187:77–83PubMedCrossRefGoogle Scholar
  26. Gratton SE, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ, Napier ME, Desimone JM (2008) The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci U S A 105:11613–11618PubMedCrossRefGoogle Scholar
  27. Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122:159–163PubMedCrossRefGoogle Scholar
  28. Hellstrand E, Lynch I, Andersson A, Drakenberg T, Dahlback B, Dawson KA, Linse S, Cedervall T (2009) Complete high-density lipoproteins in nanoparticle corona. FEBS J 276:3372–3381PubMedCrossRefGoogle Scholar
  29. Hsin YH, Chen CF, Huang S, Shih TS, Lai PS, Chueh PJ (2008) The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. Toxicol Lett 179:130–139PubMedCrossRefGoogle Scholar
  30. Huang S, Chueh PJ, Lin YW, Shih TS, Chuang SM (2009a) Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure. Toxicol Appl Pharmacol 241:182–194PubMedCrossRefGoogle Scholar
  31. Huang YF, Liu H, Xiong X, Chen Y, Tan W (2009b) Nanoparticle-mediated IgE-receptor aggregation and signaling in RBL mast cells. J Am Chem Soc 131:17328–17334PubMedCrossRefGoogle Scholar
  32. Hughes S, El Haj AJ, Dobson J (2005) Magnetic micro- and nanoparticle mediated activation of mechanosensitive ion channels. Med Eng Phys 27:754–762PubMedCrossRefGoogle Scholar
  33. Hussain S, Boland S, Baeza-Squiban A, Hamel R, Thomassen LC, Martens JA, Billon-Galland MA, Fleury-Feith J, Moisan F, Pairon JC, Marano F (2009) Oxidative stress and proinflammatory effects of carbon black and titanium dioxide nanoparticles: role of particle surface area and internalized amount. Toxicology 260:142–149PubMedCrossRefGoogle Scholar
  34. Hussain S, Thomassen LC, Ferecatu I, Borot MC, Andreau K, Martens JA, Fleury J, Baeza-Squiban A, Marano F, Boland S (2010) Carbon black and titanium dioxide nanoparticles elicit distinct apoptotic pathways in bronchial epithelial cells. Part Fibre Toxicol 7:10Google Scholar
  35. Johnston HJ, Hutchison G, Christensen FM, Peters S, Hankin S, Stone V (2010) A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity. Crit Rev Toxicol 40:328–346PubMedCrossRefGoogle Scholar
  36. Kang JL, Moon C, Lee HS, Lee HW, Park EM, Kim HS, Castranova V (2008) Comparison of the biological activity between ultrafine and fine titanium dioxide particles in RAW 264.7 cells associated with oxidative stress. J Toxicol Environ Health A 71:478–485PubMedCrossRefGoogle Scholar
  37. Kang SJ, Kim BM, Lee YJ, Hong SH, Chung HW (2009) Titanium dioxide nanoparticles induce apoptosis through the JNK/p38-caspase-8-Bid pathway in phytohemagglutinin-stimulated human lymphocytes. Biochem Biophys Res Commun 386:682–687PubMedCrossRefGoogle Scholar
  38. Kim S, Choi JE, Choi J, Chung KH, Park K, Yi J, Ryu DY (2009) Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells. Toxicol In Vitro 23:1076–1084PubMedCrossRefGoogle Scholar
  39. Koike E, Kobayashi T (2006) Chemical and biological oxidative effects of carbon black nanoparticles. Chemosphere 65:946–951PubMedCrossRefGoogle Scholar
  40. Lao F, Chen L, Li W, Ge C, Qu Y, Sun Q, Zhao Y, Han D, Chen C (2009) Fullerene nanoparticles selectively enter oxidation-damaged cerebral microvessel endothelial cells and inhibit JNK-related apoptosis. ACS Nano 3:3358–3368PubMedCrossRefGoogle Scholar
  41. Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, Wang M, Oberley T, Froines J, Nel A (2003) Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect 111:455–460PubMedCrossRefGoogle Scholar
  42. Long TC, Saleh N, Tilton RD, Lowry GV, Veronesi B (2006) Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol 40:4346–4352PubMedCrossRefGoogle Scholar
  43. Lorenz MR, Holzapfel V, Musyanovych A, Nothelfer K, Walther P, Frank H, Landfester K, Schrezenmeier H, Mailander V (2006) Uptake of functionalized, fluorescent-labeled polymeric particles in different cell lines and stem cells. Biomaterials 27:2820–2828PubMedCrossRefGoogle Scholar
  44. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A 105:14265–14270PubMedCrossRefGoogle Scholar
  45. Lynch I, Salvati A, Dawson KA (2009) Protein-nanoparticle interactions: what does the cell see? Nat Nanotechnol 4:546–547PubMedCrossRefGoogle Scholar
  46. Mailander V, Landfester K (2009) Interaction of nanoparticles with cells. Biomacromolecules 10:2379–2400PubMedCrossRefGoogle Scholar
  47. Moller W, Brown DM, Kreyling WG, Stone V (2005) Ultrafine particles cause cytoskeletal dysfunctions in macrophages: role of intracellular calcium. Part Fibre Toxicol 2:7PubMedCrossRefGoogle Scholar
  48. Nel A, Xia T, Madler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311:622–627PubMedCrossRefGoogle Scholar
  49. Nel AE, Madler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M (2009) Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8:543–557PubMedCrossRefGoogle Scholar
  50. Oberdorster G (2010) Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J Intern Med 267:89–105PubMedCrossRefGoogle Scholar
  51. Oberdorster G, Finkelstein JN, Johnston C, Gelein R, Cox C, Baggs R, Elder AC (2000) Acute pulmonary effects of ultrafine particles in rats and mice. Res Rep Health Eff Inst 96:5–74PubMedGoogle Scholar
  52. Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839PubMedCrossRefGoogle Scholar
  53. Ortner A, Wernig K, Kaisler R, Edetsberger M, Hajos F, Kohler G, Mosgoeller W, Zimmer A (2010) VPAC receptor mediated tumor cell targeting by protamine based nanoparticles. J Drug Target [Epub ahead of print]Google Scholar
  54. Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U, Schmid G, Brandau W, Jahnen-Dechent W (2007) Size-dependent cytotoxicity of gold nanoparticles. Small 3:1941–1949PubMedCrossRefGoogle Scholar
  55. Pan Y, Leifert A, Ruau D, Neuss S, Bornemann J, Schmid G, Brandau W, Simon U, Jahnen-Dechent W (2009) Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small 5:2067–2076PubMedCrossRefGoogle Scholar
  56. Park EJ, Yi J, Chung KH, Ryu DY, Choi J, Park K (2008) Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. Toxicol Lett 180:222–229PubMedCrossRefGoogle Scholar
  57. Park EJ, Yi J, Kim Y, Choi K, Park K (2009) Silver nanoparticles induce cytotoxicity by a Trojan-horse type mechanism. Toxicol In Vitro 24:872–878PubMedCrossRefGoogle Scholar
  58. Pope CA III, Verrier RL, Lovett EG, Larson AC, Raizenne ME, Kanner RE, Schwartz J, Villegas GM, Gold DR, Dockery DW (1999) Heart rate variability associated with particulate air pollution. Am Heart J 138:890–899PubMedCrossRefGoogle Scholar
  59. Rahman Q, Lohani M, Dopp E, Pemsel H, Jonas L, Weiss DG, Schiffmann D (2002) Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts. Environ Health Perspect 110:797–800PubMedCrossRefGoogle Scholar
  60. Rejman J, Oberle V, Zuhorn IS, Hoekstra D (2004) Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 377:159–169PubMedCrossRefGoogle Scholar
  61. Renwick LC, Brown D, Clouter A, Donaldson K (2004) Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup Environ Med 61:442–447PubMedCrossRefGoogle Scholar
  62. Rumelhard M, Ramgolam K, Hamel R, Marano F, Baeza-Squiban A (2007) Expression and role of EGFR ligands induced in airway cells by PM2.5 and its components. Eur Respir J 30:1064–1073PubMedCrossRefGoogle Scholar
  63. Singh S, Shi T, Duffin R, Albrecht C, Van BD, Hohr D, Fubini B, Martra G, Fenoglio I, Borm PJ, Schins RP (2007) Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. Toxicol Appl Pharmacol 222:141–151PubMedCrossRefGoogle Scholar
  64. Sniadecki NJ (2010) A tiny touch: activation of cell signaling pathways with magnetic nanoparticles. Endocrinology 151:451–457PubMedCrossRefGoogle Scholar
  65. Stoeger T, Reinhard C, Takenaka S, Schroeppel A, Karg E, Ritter B, Heyder J, Schulz H (2006) Instillation of six different ultrafine carbon particles indicates a surface area threshold dose for acute lung inflammation in mice. Environ Health Perspect 114:328–333PubMedCrossRefGoogle Scholar
  66. Stone V, Johnston H, Schins RP (2009) Development of in vitro systems for nanotoxicology: methodological considerations. Crit Rev Toxicol 39:613–626PubMedCrossRefGoogle Scholar
  67. Sydlik U, Bierhals K, Soufi M, Abel J, Schins RP, Unfried K (2006) Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R. Am J Physiol Lung Cell Mol Physiol 291:L725–L733PubMedCrossRefGoogle Scholar
  68. Tassa C, Duffner JL, Lewis TA, Weissleder R, Schreiber SL, Koehler AN, Shaw SY (2010) Binding affinity and kinetic analysis of targeted small molecule-modified nanoparticles. Bioconjug Chem 21:14–19PubMedCrossRefGoogle Scholar
  69. Thibodeau MS, Giardina C, Knecht DA, Helble J, Hubbard AK (2004) Silica-induced apoptosis in mouse alveolar macrophages is initiated by lysosomal enzyme activity. Toxicol Sci 80:34–48PubMedCrossRefGoogle Scholar
  70. Unfried K, Albrecht C, Klotz LO, Mikecz AV, Grether-Beck S, Schins RPF (2007) Cellular responses to nanoparticles: target structures and mechanisms. Nanotoxicology 1:52–71CrossRefGoogle Scholar
  71. Unfried K, Sydlik U, Bierhals K, Weissenberg A, Abel J (2008) Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation. Am J Physiol Lung Cell Mol Physiol 294:L358–L367PubMedCrossRefGoogle Scholar
  72. Val S, Hussain S, Boland S, Hamel R, Baeza-Squiban A, Marano F (2009) Carbon black and titanium dioxide nanoparticles induce pro-inflammatory responses in bronchial epithelial cells: need for multiparametric evaluation due to adsorption artifacts. Inhal Toxicol 21(Suppl 1):115–122PubMedCrossRefGoogle Scholar
  73. Vamanu CI, Cimpan MR, Hol PJ, Sornes S, Lie SA, Gjerdet NR (2008) Induction of cell death by TiO2 nanoparticles: studies on a human monoblastoid cell line. Toxicol In Vitro 22:1689–1696PubMedCrossRefGoogle Scholar
  74. Wagner S, Rothweiler F, Anhorn MG, Sauer D, Riemann I, Weiss EC, Katsen-Globa A, Michaelis M, Cinatl J Jr, Schwartz D, Kreuter J, Von BH, Langer K (2010) Enhanced drug targeting by attachment of an anti alpha v integrin antibody to doxorubicin loaded human serum albumin nanoparticles. Biomaterials 31:2388–2398PubMedCrossRefGoogle Scholar
  75. Wilson MR, Lightbody JH, Donaldson K, Sales J, Stone V (2002) Interactions between ultrafine particles and transition metals in vivo and in vitro. Toxicol Appl Pharmacol 184:172–179PubMedCrossRefGoogle Scholar
  76. Xia T, Kovochich M, Brant J, Hotze M, Sempf J, Oberley T, Sioutas C, Yeh JI, Wiesner MR, Nel AE (2006) Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6:1794–1807PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Francelyne Marano
    • 1
  • Salik Hussain
    • 1
  • Fernando Rodrigues-Lima
    • 1
  • Armelle Baeza-Squiban
    • 1
  • Sonja Boland
    • 1
  1. 1.Unit of Functional and Adaptive Biology (BFA) CNRS EAC 4413, Laboratory of Molecular and Cellular Responses to XenobioticsUniversité Paris Diderot—Paris 7Paris cedex 13France

Personalised recommendations