Abstract
Wherever nanoparticles (NPs) come in contact with a living organism, physical and chemical interactions take place between the surfaces of the NPs and biomatter, in particular proteins. When NP are exposed to biological fluids, an adsorption layer of proteins, a “protein corona” forms around the NPs. Consequently, living systems interact with the protein-coated NP rather than with a bare NP. To anticipate biological responses to NPs, we thus require comprehensive knowledge of the interactions at the bio–nano interface. In recent years, a wide variety of biophysical techniques have been employed to elucidate mechanistic aspects of NP–protein interactions. In this brief review, we present the latest findings regarding the composition of the protein corona as it forms on NPs in the blood stream. We also discuss molecular aspects of this adsorption layer and its time evolution. The current state of knowledge is summarized, and issues that still need to be addressed to further advance our understanding of NP–protein interactions are identified.
Similar content being viewed by others
References
Abbas K, Cydzik I, Del Torchio R, Farina M, Forti E, Gibson N, Holzwarth U, Simonelli F, Kreyling W (2010) Radiolabelling of TiO2 nanoparticles for radiotracer studies. J Nanopart Res 12:2435–2443
Aitken RJ, Chaudhry MQ, Boxall ABA, Hull M (2006) Manufacture and use of nanomaterials: current status in the UK and global trends. Occup Med 56:300–306
Anselmann R (2001) Nanoparticles and nanolayers in commercial applications. J Nanopart Res 3:329–336
Asha Rani PV, Low Kah Mun G, Hande MP, Valiyaveettil S (2008) Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano 3(2):279–290
Aubin-Tam M-E, Hamad-Schifferli K (2005) Gold nanoparticle–cytochrome c complexes: the effect of nanoparticle ligand charge on protein structure. Langmuir 21:12080–12084
Baier G, Costa C, Zeller A, Baumann D, Sayer C, Araujo PHH, Mailänder V, Musyanovych A, Landfester K (2011) BSA adsorption on differently charged polystyrene nanoparticles using isothermal titration calorimetry and the influence on cellular uptake. Macromol Biosci 11:628–638
Barnard AS (2006) Nanohazards: knowledge is our first defence. Nat Mater 5(4):245–248
Baron MH, Revault M, Servagent-Noinville S, Abadie J, Qui-Quampoix HJ (1999) Chymotrypsin adsorption on montmorillonite: enzymatic activity and kinetic FTIR structural analysis. J Coll Interf Sci 214:319–332
Brandes N, Welzel PB, Werner C, Kroh LW (2006) Adsorption-induced conformational changes of proteins onto ceramic particles: differential scanning calorimetry and FTIR analysis. J Coll Interf Sci 299:56–69
Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G (2010) Potential inaccurate quantitation and sizing of protein aggregates by size exclusion chromatography: essential need to use orthogonal methods to assure the quality of therapeutic protein products. J Pharmaceut Sci 99(5):2200–2208
Casals E, Pfaller T, Duschl A, Oostingh GJ, Puntes V (2010) Time evolution of the nanoparticle protein corona. ACS Nano 4(7):3623–3632
Casals E, Pfaller T, Duschl A, Oostingh GJ, Puntes VF (2011) Hardening of the nanoparticle–protein corona in metal (Au, Ag) and oxide (Fe3O4, CoO, and CeO2) nanoparticles. Small 7(24):3479–3486
Cedervall T, Lynch I, Foy M, Berggård T, Donnelly SC, Cagney G, Linse S, Dawson KA (2007a) Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew Chem Int Ed 46:5754–5756
Cedervall T, Lynch I, Lindman S, Berggård 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 USA 104(7):2050–2055
Cheng Y, Wang M, Borghs G, Chen H (2011) Gold nanoparticle dimers for plasmon sensing. Langmuir 27:7884–7891
Chithrani BD, Chan WCW (2007) Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett 7(6):1542–1550
Chittur KK (1998) FTIR/ATR for protein adsorption to biomaterial surfaces. Biomaterials 19(4–5):357–369
De Paoli Lacerda SH, Park JJ, Meuse C, Pristinski D, Becker ML, Karim A, Douglas JF (2010) Interaction of gold nanoparticles with common human blood proteins. ACS Nano 4(1):365–379
Des Rieux A, Fievez V, Garinot M, Schneider Y-J, Préat V (2006) Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release 116:1–27
Ehrenberg MS, Friedman AE, Finkelstein JN, Oberdörster G, McGrath JL (2009) The influence of protein adsorption on nanoparticle association with cultured endothelial cells. Biomaterials 30(4):603–610
Fillafer C, Friedl DS, Ilyes AK, Wirth M, Gabor F (2009) Bionanoprobes to study particle-cell interactions. J Nanosci Nanotechnol 9:3239–3245
Geiser M, Rothen-Rutishauser B, Kapp N, Schürch S, Kreyling W, Schulz H, Semmler M, Im Hof V, Heyder J, Gehr P (2005) Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect 113(11):1555–1560
Gilbert B, Huang F, Zhang H, Waychunas GA, Banfield JF (2004) Nanoparticles: strained and stiff. Science 305(5684):651–654
Goodman CM, McCusker CD, Yilmaz T, Rotello VM (2004) Toxicity of gold nanoparticles functionalized with cationic and anionic side chains. Bioconjug Chem 15:897–900
Greenfield NJ (1999) Applications of circular dichroism in protein and peptide analysis. Trends Anal Chem 18(4):236–244
Greulich C, Kittler S, Epple M, Muhr G, Köller M (2009) Studies on the biocompatibility and the interaction of silver nanoparticles with human mesenchymal stem cells (hMSCs). Langenbecks Arch Surg 394:495–502
Handy RD, Henry TB, Scrown TM, Johnston BD, Tyler CR (2008a) Manufactured nanoparticles: their uptake and effects on fish—a mechanistic analysis. Ecotoxicology 17(5):396–409
Handy RD, von der Kammer F, Lead JR, Hassellöv M, Owen R, Crane M (2008b) The ecotoxicology and chemistry of manufactured nanoparticles. Ecotoxicology 17:287–314
Harris JM, Martin NE, Modi M (2001) Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 40:539–551
Havel HA (1996) Spectroscopic methods for determining protein structure in solution. Wiley-VCH, New York
Jeong SK, Kwon MS, Lee EY, Lee HJ, Cho SY, Kim H, Yoo JS, Omenn GS, Aebersold R, Hanash S, Paik YK (2009) BiomarkerDigger: a versatile disease proteome database and analysis platform for the identification of plasma cancer biomarkers. Proteomics 9(14):3729–3740
Jiang X, Weise S, Hafner M, Röcker C, Zhang F, Parak WJ, Nienhaus GU (2010) Quantitative analysis of the protein corona on FePt nanoparticles formed by transferrin binding. J R Soc Interface 7:S5–S13
Kah JC, Wong KY, Neoh KG, Song JH, Fu JW, Mhaisalkar S, Olivo M, Sheppard CJ (2009) Critical parameters in the pegylation of gold nanoshells for biomedical applications: an in vitro macrophage study. J Drug Target 17:181–193
Keller KH (2007) Nanotechnology and society. J Nanopart Res 9:5–10
Kelly SM, Jess TJ, Price NC (2005) How to study proteins by circular dichroism. Biochim Biophys Acta 1751:119–139
Kittler S, Greulich C, Diendorf J, Köller M, Epple M (2010a) The toxicity of silver nanoparticles increases during storage due to slow dissolution under release of silver ions. Chem Mater 22(16):4548–4554
Kittler S, Greulich C, Gebauer JS, Diendorf J, Treuel L, Ruiz L, Gonzalez-Calbet JM, Vallet-Regi M, Zellner R, Köller M, Epple M (2010b) The influence of proteins on the dispersability and cell-biological activity of silver nanoparticles. J Mater Chem 20(3):512–518
Klein J (2007) Probing the interactions of proteins and nanoparticles. Proc Natl Acad Sci USA 104(7):2029–2030
Kreyling WG, Semmler M, Möller W (2004) Dosimetry and toxicology of ultrafine particles. J Aerosol Med 17(2):140–152
Leszczynski J (2010) Bionanoscience: nano meets bio at the interface. Nat Nanotechnol 5(9):633–634
Linse S, Cabaleiro-Lago C, Xue W-F, Lynch I, Lindman S, Thulin E, Radford SE, Dawson KA (2007) Nucleation of protein fibrillation by nanoparticles. Proc Natl Acad Sci USA 104(21):8691–8696
Liu L, Xu K, Wang H, Tan PKJ, Fan W, Venkatraman SS, Li L, Yang Y-Y (2009) Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent. Nat Nanotechnol 4:457–463
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 USA 105(38):14265–14270
Lundqvist M, Stigler J, Cedervall T, Berggård T, Flanagan MB, Lynch I, Elia G, Dawson K (2011) The evolution of the protein corona around nanoparticles: a test study. ACS Nano 5(9):7503–7509
Lunov O, Syrovets T, Röcker C, Tron K, Nienhaus GU, Rasche V, Mailänder V, Landfester K, Simmet T (2010) Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes. Biomaterials 31(34):9015–9022
Lunov O, Zablotskii V, Syrovets T, Röcker C, Tron K, Nienhaus GU, Simmet T (2011) Modeling receptor-mediated endocytosis of polymer-functionalized iron oxide nanoparticles by human macrophages. Biomaterials 32(2):547–555
Lynch I (2007) Are there generic mechanisms governing interactions between nanoparticles and cells? Random epitope mapping for the outer layer of the protein-material interface. Physica A 373:511–520
Lynch I, Dawson KA, Linse S (2006) Detecting cryptic epitopes created by nanoparticles. Sci STKE 2006(327):14
Maffre P, Nienhaus K, Amin F, Parak WJ, Nienhaus GU (2011) Characterization of protein adsorption onto FePt nanoparticles using dual-focus fluorescence correlation spectroscopy. Beilstein J Nanotechnol 2:374–383
Mátyus L, Szöllösi J, Jenei A (2006) Steady-state fluorescence quenching applications for studying protein structure and dynamics. J Photochem Photobiol B: Biol 83:223–236
Maynard AD, Aitken RJ, Butz T, Colvin V, Donaldsen K, Oberdörster G, Philbert MA, Ryan J, Seaton A, Stone V, Tinkle SS, Tran L, Walker NJ, Warheit DB (2006) Safe handling of nanotechnology. Nature 444:267–269
Medintz IL, Konnert JH, Clapp AR, Stanish I, Twing ME, Mattoussi H, Mauro JM, Deschamps JR (2004) A fluorescence resonance energy transfer-derived structure of a quantum dot-protein bioconjugate nanoassembly. Proc Natl Acad Sci USA 101(26):9612–9617
Min Y, Akbulut M, Kristiansen K, Golan Y, Israelachvili J (2008) The role of interparticle and external forces in nanoparticle assembly. Nat Mater 7(7):527–538
Monopoli MP, Walczyk D, Campbell A, Elia G, Lynch I, Bombelli FB, Dawson KA (2011) Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. J Am Chem Soc 133(8):2525–2534
Mori S, Barth HG (1999) Size exclusion chromatography. Springer, Berlin
Nativo P, Prior IA, Brust M (2008) Uptake and intracellular fate of surface-modified gold nanoparticles. ACS Nano 2:1639–1644
Nel A, Xia T, Mädler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311:622–627
Nel AE, Mädler 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(7):543–557
Nienhaus GU (ed) (2005) Protein-ligand interactions: methods and applications. Humana Press, New York
Niidome T, Yamagata M, Okamoto Y, Akiyama Y, Takahashi H, Kawano T, Katayama Y, Niidome Y (2006) PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release 114:343–347
Oberdörster G (2010) Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J Intern Med 267(1):89–105
Oberdörster G, Maynard A, Donaldson K, Castranova V, Fitzpatrick J, Ausman K, Carter J, Karn B, Kreyling W, Lai D, Olin S, Monteiro-Riviere N, Warheit D, Yang H (2005a) Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol 2(8):1–35
Oberdörster G, Oberdörster E, Oberdörster J (2005b) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823–839
Organization for Economic Co-operation and Development (OECD) (2008) Current developments/activities on the safety of manufactured nanomaterials. OECD environment, health and safety publication series on the safety of manufactured nanomaterials. OECD, Paris
Owen R, Depledge M (2005) Nanotechnology in the environment: risks and rewards. Mar Pollut Bull 50:609–612
Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102
Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U (2007) Size-dependent cytotoxicity of gold nanoparticles. Small 3:1941–1949
Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WAH, Seaton A, Stone V, Brown S, Macnee W, Donaldson K (2008) Carbon nanotubes introduced into the abdominal cavity of mice show asbestoslike pathogenicity in a pilot study. Nature 3:423–428
Printz M, Friess W (2012) Simultaneous detection and analysis of protein aggregation and protein unfolding by size exclusion chromatography with post column addition of the fluorescent dye BisANS. J Pharmaceut Sci 101(2):826–837
Roach P, Farrar D, Perry CC (2006) Surface tailoring for controlled protein adsorption: effect of topography at the nanometer scale and chemistry. J Am Chem Soc 128(12):3939–3945
Röcker C, Pötzl M, Zhang F, Parak WJ, Nienhaus GU (2009) A quantitative fluoresence study of protein monolayer formation on colloidal nanoparticles. Nat Nanotechnol 4(9):577–580
Roco MC (2008) The journal of nanoparticle research at 10 years. J Nanopart Res 10(1):1–2
Rodriguez CE, Fukuto JM, Taguchi K, Froines J, Cho AK (2005) The interactions of 9,10-phenantrenequinone with glyceraldehyde-3-phosphatedehydrogenase (GAPDH), a potential site for toxic actions. Chem Biol Interact 155(1):97–110
Rothen-Rutishauser B, Kiama S, Gehr P (2005) A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am J Respir Cell Mol Biol 32(4):281–289
Royer CA (2006) Probing protein folding and conformational transitions with fluorescence. Chem Rev 106:1769–1784
Schlücker S (2008) Gezielte Proteinlokalisierung. Biophotonik 3:18–20
Semmler-Behnke M, Takenaka S, Fertsch S, Wenk A, Seitz J, Mayer P, Oberdoerster G, Kreyling WG (2007) Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium. Environ Health Perspect 115(5):728–733
Service RF (2006) Priorities needed for nano-risk research and development. Science 314:45
Shang L, Wang Y, Jiang J, Dong S (2007) pH-dependent protein conformational changes in albumin—gold nanoparticle bioconjugates: a spectroscopic study. Langmuir 23:2714–2721
Shang W, Nuffer JH, Muñiz-Papandrea VA, Colón W, Siegel RW, Dordick JS (2009) cytochrome c on silica nanoparticles: influence of nanoparticle size on protein structure, stability, and activity. Small 5(4):470–476
Shang L, Brandholt S, Stockmar F, Trouillet V, Bruns M, Nienhaus GU (2011a) Effect of protein adsorption on the fluorescence of ultrasmall gold nanoclusters. Small. doi:10.1002/smll.201101353
Shang L, Doerlich RM, Brandholt S, Schneider R, Trouillet V, Bruns M, Gerthsen D, Nienhaus GU (2011b) Facile preparation of water-soluble fluorescent gold nanoclusters for cellular imaging applications. Nanoscale 3(5):2009–2014
Shang L, Dong S, Nienhaus GU (2011c) Ultra-small fluorescent metal nanoclusters: synthesis and biological applications. Nano Today 6(4):401–418
Shao M, Lu L, Wang H, Luo S, Duo Duo Ma D (2009) Microfabrication of a new sensor based on silver and silicon nanomaterials, and its application to the enrichment and detection of bovine serum albumin via surface-enhanced Raman scattering. Microchim Acta 164:157–160
Tenzer S, Docter D, Rosfa S, Wlodarski A, Kuharev J, Rekik A, Knauer SK, Bantz C, Nawroth T, Bier C, Sirirattanapan J, Mann W, Treuel L, Zellner R, Maskos M, Schild H, Stauber RH (2011) Nanoparticle size is a critical physicochemical determinant of the human blood plasma corona: a comprehensive quantitative proteomic analysis. ACS Nano 5(9):7155–7167
Treuel L, Malissek M, Gebauer JS, Zellner R (2010) The influence of surface composition of nanoparticles on their interactions with serum albumin. Chem Phys Chem 11(14):3093–3099
Vertegel AA, Siegel RW, Dordic JS (2004) Silica nanoparticle size influences the structure and enzymatic activity of adsorbed lysozyme. Langmuir 20(16):6800–6807
Vogt A, D’Angelo C, Oswald F, Denzel A, Mazel CH, Matz MV, Ivanchenko S, Nienhaus GU, Wiedenmann J (2008) A green fluorescent protein with photoswitchable emission from the deep sea. PLoS One 3(11):1–8
Wang T, Bai J, Jiang X, Nienhaus GU (2012) Cellular uptake of nanoparticles by membrane penetration: a study combining confocal microscopy with FTIR spectroelectrochemistry. ACS Nano. doi:10.1021/nn203892h
Watari F, Takashi N, Yokoyama A, Uo M, Akasaka M, Sato Y, Abe S, Totsuka Y, Tohji K (2009) Material nanosizing effect on living organism: non-specific, biointeractive, physical size effects. J R Soc Interf 6:371–388
Wiedenmann J, Schenk A, Röcker C, Girod A, Spindler KD, Nienhaus GU (2002) A far-red fluorescent protein with fast maturation and reduced oligomerization tendency from Entacmaea quadricolor (Anthozoa, Actinaria). Prod Natl Acad Sci USA 99:11646–11651
Wiedenmann J, Ivanchenko S, Oswald F, Nienhaus GU (2004) Identification of GFP-like proteins in nonbioluminescent, azooxanthellate anthozoa opens new perspectives for bioprospecting. Mar Biotechnol 6:270–277
Wiesner MR, Lowry GV, Alvarez P, Dionysiou D, Biswas P (2006) Assessing the risks of manufactured nanomaterials. Environ Sci Technol 40:4336–4345
Yan M, Du J, Gu Z, Liang M, Hu Y, Zhang W, Priceman S, Wu L, Hong Zhou Z, Liu H, Segura T, Tang Y, Lu Y (2009) A novel intracellular protein delivery platform based on single-protein nanocapsules. Nat Nanotechnol 5:48–53
Ye-Qin Z, Wang Y-F, Jiang X-D (2008) The application of nanoparticles in biochips. Recent Patents Biotechnol 2(1):55–59
Zhang J, Yan YB (2005) Probing conformational changes of proteins by quantitative second-derivative infrared spectroscopy. Anal Biochem 340:89–98
Zhou HS, Aoki S, Honma I, Hirasawa M, Nagamune T, Komiyama H (1997) Conformational change of protein cytochrome b-562 adsorbed on colloidal gold particles; absorption band shift. Chem Commun. 605–606
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Center for Functional Nanostructures (CFN) and the Priority Program SPP1313.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Treuel, L., Nienhaus, G.U. Toward a molecular understanding of nanoparticle–protein interactions. Biophys Rev 4, 137–147 (2012). https://doi.org/10.1007/s12551-012-0072-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12551-012-0072-0