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Unveiling the pitfalls of the protein corona of polymeric drug nanocarriers

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Abstract

The protein corona is a natural protein layer spontaneously formed around nanomaterials when exposed to biological media. This layer can alter the nanosystems’ biological performance, particularly their tissue accumulation, cellular uptake, clearance by the immune system, toxicity, and even the release profile of their payloads. Hence, the characterization of this protein layer has become a critical step when developing a new nanomedicine. The modification of the nanosystem fate by the protein corona, systematically ignored in the vast majority of the nanotechnology-based research, may have contributed to the low in vitro/in vivo correlation. Actually, the protein corona of polymeric nanosystems has been scarcely studied in the literature, and most studies have been focused instead on metallic nanoparticles and liposomes. In this review, we analyzed the influence of the physicochemical properties and composition of the polymeric nanosystems on the protein layer deposited around them. In addition, we present some recommendations on how to perform the protein corona studies of polymeric nanoparticles, which, hopefully, will contribute to obtain more reliable and reproducible data in the future.

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References

  1. Lynch I, Cedervall T, Lundqvist M, Cabaleiro-Lago C, Linse S, Dawson KA. The nanoparticle-protein complex as a biological entity; a complex fluids and surface science challenge for the 21st century. Adv Colloid Interf Sci. 2007;134–135:167–74.

    Article  CAS  Google Scholar 

  2. Mahmoudi M, Lohse SE, Murphy CJ, Fathizadeh A, Montazeri A, Suslick KS. Variation of protein corona composition of gold nanoparticles following plasmonic heating. Nano Lett. 2014;14:6–12.

    Article  CAS  PubMed  Google Scholar 

  3. Mahmoudi M, Bertrand N, Zope H, Farokhzad OC. Emerging understanding of the protein corona at the nano-bio interfaces. Nano Today. 2016;11:817–32.

    Article  CAS  Google Scholar 

  4. Salameh S, Van Der Veen MA, Kappl M, Van Ommen JR. Contact forces between single metal oxide nanoparticles in gas-phase applications and processes. Langmuir. 2017;33:2477–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pareek V, Bhargava A, Bhanot V, Gupta R, Jain N, Panwar J. Formation and characterization of protein corona around nanoparticles: a review. J Nanosci Nanotechnol. 2018;18:6653–70.

    Article  CAS  PubMed  Google Scholar 

  6. Tyrrell DA, Richardson VJ, Ryman BE. The effect of serum protein fractions on liposome cell interactions in cultured cells and the perfused rat liver. Biochim Biophys Acta. 1977;497:469–80.

    Article  CAS  PubMed  Google Scholar 

  7. Kiwada H, Miyajima T, Kato Y. Studies on the uptake mechanism factor of liposomes for liver by perfused uptake in serum rat liver. II. An indispensable factor for liver uptake in serum. Chem Pharm Bull. 1987;35:1189–95.

    Article  CAS  PubMed  Google Scholar 

  8. Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, et al. Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci. 2007;104:2050–5.

    Article  CAS  PubMed  Google Scholar 

  9. Hadjidemetriou M, Kostarelos K. Nanomedicine: evolution of the nanoparticle corona. Nat Nanotechnol. 2017;12:288–90.

    Article  CAS  PubMed  Google Scholar 

  10. Monopoli MP, Walczyk D, Campbell A, Elia G, Lynch I, Baldelli Bombelli F, et al. Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. J Am Chem Soc. 2011;133:2525–34.

    Article  CAS  PubMed  Google Scholar 

  11. Charbgoo F, Nejabat M, Abnous K, Soltani F, Taghdisi SM, Alibolandi M, et al. Gold nanoparticle should understand protein corona for being a clinical nanomaterial. J Control Release. 2018;272:39–53.

    Article  CAS  PubMed  Google Scholar 

  12. Monopoli MP, Åberg C, Salvati A, Dawson KA. Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol. 2012;7:779–86.

    Article  CAS  PubMed  Google Scholar 

  13. Vroman L, Adams AL, Fischer GC, Munoz PC. Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces. Blood. 1980;55:156–9.

    Article  CAS  PubMed  Google Scholar 

  14. Casals E, Pfaller T, Duschl A, Oostingh GJ, Puntes V. Time evolution of the nanoparticle protein corona. ACS Nano. 2010;4:3623–32.

    Article  CAS  PubMed  Google Scholar 

  15. Cedervall T, Lynch I, Foy M, Berggård T, Donnelly SC, Cagney G, et al. Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew Chem Int Ed Eng. 2007;46:5754–6.

    Article  CAS  Google Scholar 

  16. Mahon E, Salvati A, Baldelli Bombelli F, Lynch I, Dawson KA. Designing the nanoparticle-biomolecule interface for “targeting and therapeutic delivery”. J Control Release. 2012;161:164–74.

    Article  CAS  PubMed  Google Scholar 

  17. Kokkinopoulou M, Simon J, Landfester K, Mailänder V, Lieberwirth I. Visualization of the protein corona: towards a biomolecular understanding of nanoparticle-cell-interactions. Nanoscale. 2017;9:8858–70.

    Article  CAS  PubMed  Google Scholar 

  18. Weber C, Simon J, Mailänder V, Morsbach S, Landfester K. Preservation of the soft protein corona in distinct flow allows identification of weakly bound proteins. Acta Biomater. 2018;76:217–24.

    Article  CAS  PubMed  Google Scholar 

  19. Tenzer S, Docter D, Kuharev J, Musyanovych A, Fetz V, Hecht R, et al. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol. 2013;8:772–81.

    Article  CAS  PubMed  Google Scholar 

  20. Luck M, Paulke B-R, Schroder W, Blunk T, Müller RH. Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics. J Biomed Mater Res. 1998;39:478–85.

    Article  CAS  PubMed  Google Scholar 

  21. Simon J, Müller LK, Kokkinopoulou M, Lieberwirth I, Morsbach S, Landfester K, et al. Exploiting the biomolecular corona: pre-coating of nanoparticles enables controlled cellular interactions. Nanoscale. 2018;10:10731–9.

    Article  CAS  PubMed  Google Scholar 

  22. Tonigold M, Simon J, Estupiñán D, Kokkinopoulou M, Reinholz J, Kintzel U, et al. Pre-adsorption of antibodies enables targeting of nanocarriers despite a biomolecular corona. Nat Nanotechnol. 2018;13:862–9.

    Article  CAS  PubMed  Google Scholar 

  23. Danner A, Schöttler S, Alexandrino E, Hammer S, Landfester K, Mailänder V, et al. Phosphonylation controls the protein corona of multifunctional polyglycerol-modified nanocarriers. Macromol Biosci. 2019;19:e1800468.

    Article  PubMed  CAS  Google Scholar 

  24. Allémann E, Gravel P, Leroux JC, Balant L, Gurny R. Kinetics of blood component adsorption on poly(D,L-lactic acid) nanoparticles: evidence of complement C3 component involvement. J Biomed Mater Res. 1997;37:229–34.

    Article  PubMed  Google Scholar 

  25. Gref R, Lück M, Quellec P, Marchand M, Dellacherie E, Harnisch S, et al. “Stealth” corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B: Biointerfaces. 2000;18:301–13.

    Article  CAS  PubMed  Google Scholar 

  26. Pederzoli F, Tosi G, Genovese F, Belletti D, Vandelli MA, Ballestrazzi A, et al. Qualitative and semiquantitative analysis of the protein coronas associated to different functionalized nanoparticles. Nanomedicine. 2018;13:407–22.

    Article  CAS  PubMed  Google Scholar 

  27. Gossmann R, Fahrländer E, Hummel M, Mulac D, Brockmeyer J, Langer K. Comparative examination of adsorption of serum proteins on HSA- and PLGA-based nanoparticles using SDS-PAGE and LC-MS. Eur J Pharm Biopharm. 2015;93:80–7.

    Article  CAS  PubMed  Google Scholar 

  28. Lemarchand C, Gref R, Passirani C, Garcion E, Petri B, Müller R, et al. Influence of polysaccharide coating on the interactions of nanoparticles with biological systems. Biomaterials. 2006;27:108–18.

    Article  CAS  PubMed  Google Scholar 

  29. Labarre D, Vauthier C, Chauvierre C, Petri B, Müller R, Chehimi MM. Interactions of blood proteins with poly (isobutylcyanoacrylate) nanoparticles decorated with a polysaccharidic brush. Biomaterials. 2005;26:5075–84.

    Article  CAS  PubMed  Google Scholar 

  30. Kim HR, Andrieux K, Delomenie C, Chacun H, Appel M, Desmaële D, et al. Analysis of plasma protein adsorption onto PEGylated nanoparticles by complementary methods: 2-DE, CE and Protein Lab-on-chip® system. Electrophoresis. 2007;28:2252–61.

    Article  CAS  PubMed  Google Scholar 

  31. Naidu PSR, Norret M, Smith NM, Dunlop SA, Taylor NL, Fitzgerald M, et al. The protein corona of PEGylated PGMA-based nanoparticles is preferentially enriched with specific serum proteins of varied biological function. Langmuir. 2017;33:12926–33.

    Article  CAS  PubMed  Google Scholar 

  32. Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev. 2009;61:428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nagayama S, Ogawara K i, Fukuoka Y, Higaki K, Kimura T. Time-dependent changes in opsonin amount associated on nanoparticles alter their hepatic uptake characteristics. Int J Pharm. 2007;342:215–21.

    Article  CAS  PubMed  Google Scholar 

  34. Wang H, Lin Y, Nienhaus K, Nienhaus GU. The protein corona on nanoparticles as viewed from a nanoparticle-sizing perspective. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2018;10:e1500.

    Article  PubMed  Google Scholar 

  35. Corbo C, Molinaro R, Parodi A, Toledano Furman NE, Salvatore F, Tasciotti E. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. Nanomedicine. 2016;11:81–100.

    Article  CAS  PubMed  Google Scholar 

  36. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A. 2008;105:14265–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pulido-Reyes G, Leganes F, Fernández-Piñas F, Rosal R. Bio-nano interface and environment: a critical review. Environ Toxicol Chem. 2017;36:3181–93.

    Article  CAS  PubMed  Google Scholar 

  38. Caracciolo G. Clinically approved liposomal nanomedicines: lessons learned from the biomolecular corona. Nanoscale. 2018;10:4167–72.

    Article  CAS  PubMed  Google Scholar 

  39. Mandal B, Bhattacharjee H, Mittal N, Sah H, Balabathula P, Thoma LA, et al. Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine: NBM. 2013;9:474–91.

    Article  CAS  Google Scholar 

  40. Schöttler S, Landfester K, Mailänder V. Controlling the stealth effect of nanocarriers through understanding the protein corona. Angew Chem Int Ed Eng. 2016;55:8806–15.

    Article  CAS  Google Scholar 

  41. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102.

    Article  CAS  PubMed  Google Scholar 

  42. Cordeiro AS, Alonso MJ, de la Fuente M. Nanoengineering of vaccines using natural polysaccharides. Biotechnol Adv. 2015;33:1279–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Csaba NS, Sánchez A, Alonso MJ Preparation of poly (lactic acid) (PLA) and poly (ethylene oxide) (PEO) nanoparticles as carriers for gene delivery. Cold Spring Harb Protoc. 2010. https://doi.org/10.1101/pdb.prot5468.

  44. Calvo P, Thomas C, Alonso MJ, Vila-Jato J, Robinson JR. Study of the mechanism of interaction of poly(ϵ-caprolactone) nanocapsules with the cornea by confocal laser scanning microscopy. Int J Pharm. 1994;103:283–91.

    Article  CAS  Google Scholar 

  45. Cadete A, Olivera A, Besev M, Dhal PK, Gonçalves L, Almeida AJ, et al. Self-assembled hyaluronan nanocapsules for the intracellular delivery of anticancer drugs. Sci Rep. 2019;9:11565.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Ledo AM, Sasso MS, Bronte V, Marigo I, Boyd BJ, Garcia-Fuentes M, et al. Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. J Control Release. 2019;295:60–73.

    Article  CAS  PubMed  Google Scholar 

  47. Reimondez-Troitiño S, González-Aramundiz JV, Ruiz-Bañobre J, López-López R, Alonso MJ, Csaba N, et al. Versatile protamine nanocapsules to restore miR-145 levels and interfere tumor growth in colorectal cancer cells. Eur J Pharm Biopharm. 2019;142:449–59.

    Article  PubMed  CAS  Google Scholar 

  48. Correia-Pinto JF, Csaba N, Schiller JT, Alonso MJ. Chitosan-poly (I:C)-PADRE based nanoparticles as delivery vehicles for synthetic peptide vaccines. Vaccines. 2015;3:730–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Thwala LN, Beloqui A, Csaba NS, González-Touceda D, Tovar S, Dieguez C, et al. The interaction of protamine nanocapsules with the intestinal epithelium: a mechanistic approach. J Control Release. 2016;243:109–20.

    Article  CAS  PubMed  Google Scholar 

  50. Mirshafiee V, Mahmoudi M, Lou K, Cheng J, Kraft ML. Protein corona significantly reduces active targeting yield. Chem Commun. 2013;49:2557–9.

    Article  CAS  Google Scholar 

  51. Jain P, Pawar RS, Pandey RS, Madan J, Pawar S, Lakshmi PK, et al. In-vitro in-vivo correlation (IVIVC) in nanomedicine: is protein corona the missing link? Biotechnol Adv. 2017;35:889–904.

    Article  CAS  PubMed  Google Scholar 

  52. Mirshafiee V, Kim R, Park S, Mahmoudi M, Kraft ML. Impact of protein pre-coating on the protein corona composition and nanoparticle cellular uptake. Biomaterials. 2016;75:295–304.

    Article  CAS  PubMed  Google Scholar 

  53. Francia V, Yang K, Deville S, Reker-Smit C, Nelissen I, Salvati A. Corona composition can affect the mechanisms cells use to internalize nanoparticles. ACS Nano. 2019;13:11107–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang K, Mesquita B, Horvatovich P, Salvati A. Tuning liposome composition to modulate the corona forming in human serum and uptake by cells. Acta Biomater. 2020;S1742-7061:30097–0. https://doi.org/10.1016/j.actbio.2020.02.018.

    Article  CAS  Google Scholar 

  55. Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, et al. Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol. 2013;31:638–46.

    Article  CAS  PubMed  Google Scholar 

  56. Lara S, Perez-Potti A, Herda LM, Adumeau L, Dawson KA, Yan Y. Differential recognition of nanoparticle protein corona and modified low-density lipoprotein by macrophage receptor with collagenous structure. ACS Nano. 2018;12:4930–7.

    Article  CAS  PubMed  Google Scholar 

  57. Wolfram J, Suri K, Yang Y, Shen J, Celia C, Fresta M, et al. Shrinkage of pegylated and non-pegylated liposomes in serum. Colloids Surf B: Biointerfaces. 2014;114:294–300.

    Article  CAS  PubMed  Google Scholar 

  58. Almalik A, Benabdelkamel H, Masood A, Alanazi IO, Alradwan I, Majrashi MA, et al. Hyaluronic acid coated chitosan nanoparticles reduced the immunogenicity of the formed protein corona. Sci Rep. 2017;7:10542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Dobrovolskaia MA, Aggarwal P, Hall JB, Mcneil SE. Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. Mol Pharm. 2008;5:487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Walkey CD, Olsen JB, Guo H, Emili A, Chan WCW. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. 2012;134:2139–47.

    Article  CAS  PubMed  Google Scholar 

  61. Chithrani BD, Chan WCW. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett. 2007;7:1542–50.

    Article  CAS  PubMed  Google Scholar 

  62. Pozzi D, Caracciolo G, Capriotti AL, Cavaliere C, Piovesana S, Colapicchioni V, et al. A proteomics-based methodology to investigate the protein corona effect for targeted drug delivery. Mol BioSyst. 2014;10:2815–9.

    Article  CAS  PubMed  Google Scholar 

  63. Ritz S, Schöttler S, Kotman N, Baier G, Musyanovych A, Kuharev J, et al. Protein corona of nanoparticles: distinct proteins regulate the cellular uptake. Biomacromolecules. 2015;16:1311–21.

    Article  CAS  PubMed  Google Scholar 

  64. Furumoto K, Ogawara K, Nagayama S, Takakura Y, Hashida M, Higaki K, et al. Important role of serum proteins associated on the surface of particles in their hepatic disposition. J Control Release. 2002;83:89–96.

    Article  CAS  PubMed  Google Scholar 

  65. Caracciolo G, Palchetti S, Colapicchioni V, Digiacomo L, Pozzi D, Capriotti AL, et al. Stealth effect of biomolecular corona on nanoparticle uptake by immune cells. Langmuir. 2015;31:10764–73.

    Article  CAS  PubMed  Google Scholar 

  66. Coty JB, Eleamen Oliveira E, Vauthier C. Tuning complement activation and pathway through controlled molecular architecture of dextran chains in nanoparticle corona. Int J Pharm. 2017;532:769–78.

    Article  CAS  PubMed  Google Scholar 

  67. Schöttler S, Becker G, Winzen S, Steinbach T, Mohr K, Landfester K, et al. Protein adsorption is required for stealth effect of poly (ethylene glycol)- and poly (phosphoester)-coated nanocarriers. Nat Nanotechnol. 2016;11:372–7.

    Article  PubMed  CAS  Google Scholar 

  68. Landgraf L, Christner C, Storck W, Schick I, Krumbein I, Dähring H, et al. A plasma protein corona enhances the biocompatibility of Au@Fe3O4 janus particles. Biomaterials. 2015;68:77–88.

    Article  CAS  PubMed  Google Scholar 

  69. Fleischer CC, Payne CK. Secondary structure of corona proteins determines the cell surface receptors used by nanoparticles. J Phys Chem B. 2014;118:14017–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ghazaryan A, Landfester K, Mailänder V. Protein deglycosylation can drastically affect the cellular uptake. Nanoscale. 2019;11:10727–37.

    Article  CAS  PubMed  Google Scholar 

  71. Wan S, Kelly PM, Mahon E, Stöckmann H, Rudd PM, Caruso F, et al. The “sweet” side of the protein corona: effects of glycosylation on nanoparticle–cell interactions. ACS Nano. 2015;9:2157–66.

    Article  CAS  PubMed  Google Scholar 

  72. Vu VP, Gifford GB, Chen F, Benasutti H, Wang G, Groman EV, et al. Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles. Nat Nanotechnol. 2019;14:260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cox A, Andreozzi P, Dal Magro R, Fiordaliso F, Corbelli A, Talamini L, et al. Evolution of nanoparticle protein corona across the blood–brain barrier. ACS Nano. 2018;12:7292–300.

    Article  CAS  PubMed  Google Scholar 

  74. Hellstrand E, Lynch I, Andersson A, Drakenberg T, Dahlbäck B, Dawson KA, et al. Complete high-density lipoproteins in nanoparticle corona. FEBS J. 2009;276:3372–81.

    Article  CAS  PubMed  Google Scholar 

  75. Barrán-Berdón AL, Pozzi D, Caracciolo G, Capriotti AL, Caruso G, Cavaliere C, et al. Time evolution of nanoparticle-protein corona in human plasma: relevance for targeted drug delivery. Langmuir. 2013;29:6485–94.

    Article  PubMed  CAS  Google Scholar 

  76. Kreuter J, Hekmatara T, Dreis S, Vogel T, Gelperina S, Langer K. Covalent attachment of apolipoprotein A-I and apolipoprotein B-100 to albumin nanoparticles enables drug transport into the brain. J Control Release. 2007;118:54–8.

    Article  CAS  PubMed  Google Scholar 

  77. Kim HR, Andrieux K, Gil S, Taverna M, Chacun H, Desmaële D, et al. Translocation of poly (ethylene glycol-co-hexadecyl) cyanoacrylate nanoparticles into rat brain endothelial cells: role of apolipoproteins on receptor-medicted endocytosis. Biomacromolecules. 2007;8:793–9.

    Article  CAS  PubMed  Google Scholar 

  78. Prapainop K, Wentworth P. A shotgun proteomic study of the protein corona associated with cholesterol and atheronal-B surface-modified quantum dots. Eur J Pharm Biopharm. 2011;77:353–9.

    Article  CAS  PubMed  Google Scholar 

  79. Capjak I, Goreta SŠ, Jurašin DD, Vrček IV. How protein coronas determine the fate of engineered nanoparticles in biological environment. Arh Hig Rada Toksikol. 2017;68:245–53.

    Article  CAS  PubMed  Google Scholar 

  80. Bertoli F, Garry D, Monopoli MP, Salvati A, Dawson KA. The intracellular destiny of the protein corona: a study on its cellular internalization and evolution. ACS Nano. 2016;10:10471–9.

    Article  CAS  PubMed  Google Scholar 

  81. Behzadi S, Serpooshan V, Sakhtianchi R, Müller B, Landfester K, Crespy D, et al. Protein corona change the drug release profile of nanocarriers: the “overlooked” factor at the nanobio interface. Colloids Surf B: Biointerfaces. 2014;123:143–9.

    Article  CAS  PubMed  Google Scholar 

  82. Abstiens K, Maslanka Figueroa S, Gregoritza M, Goepferich AM. Interaction of functionalized nanoparticles with serum proteins and its impact on colloidal stability and cargo leaching. Soft Matter. 2019;15:709–20.

    Article  CAS  PubMed  Google Scholar 

  83. Wang H, Ma R, Nienhaus K, Nienhaus GU. Formation of a monolayer protein corona around polystyrene nanoparticles and implications for nanoparticle agglomeration. Small. 2019;15:e1900974.

    Article  PubMed  CAS  Google Scholar 

  84. Gunnarsson SB, Bernfur K, Mikkelsen A, Cedervall T. Analysis of nanoparticle biomolecule complexes. Nanoscale. 2018;10:4246–57.

    Article  CAS  PubMed  Google Scholar 

  85. Bonvin D, Aschauer U, Alexander DTL, Chiappe D, Moniatte M, Hofmann H, et al. Protein corona: impact of lymph versus blood in a complex in vitro environment. Small. 2017;13:1700409.

    Article  CAS  Google Scholar 

  86. Partikel K, Korte R, Stein NC, Mulac D, Herrmann FC, Humpf H-U, et al. Effect of nanoparticle size and PEGylation on the protein corona of PLGA nanoparticles. Eur J Pharm Biopharm. 2019;141:70–80.

    Article  CAS  PubMed  Google Scholar 

  87. Lynch I, Dawson KA. Protein-nanoparticle interactions. Nano Today. 2008;3:40–7.

    Article  CAS  Google Scholar 

  88. Moyano DF, Saha K, Prakash G, Yan B, Kong H, Yazdani M, et al. Fabrication of corona-free nanoparticles with tunable hydrophobicity. ACS Nano. 2014;8:6748–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Glancy D, Zhang Y, Wu JLY, Ouyang B, Ohta S, Chan WCW. Characterizing the protein corona of sub-10 nm nanoparticles. J Control Release. 2019;304:102–10.

    Article  CAS  PubMed  Google Scholar 

  90. Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 2006;6:662–8.

    Article  CAS  PubMed  Google Scholar 

  91. Gessner A, Lieske A, Paulke BR, Müller RH. Influence of surface charge density on protein adsorption on polymeric nanoparticles: analysis by two-dimensional electrophoresis. Eur J Pharm Biopharm. 2002;54:165–70.

    Article  CAS  PubMed  Google Scholar 

  92. Wang CF, Mäkilä EM, Bonduelle C, Rytkönen J, Raula J, Almeida S, et al. Functionalization of alkyne-terminated thermally hydrocarbonized porous silicon nanoparticles with targeting peptides and antifouling polymers: effect on the human plasma protein adsorption. ACS Appl Mater Interfaces. 2015;7:2006–15.

    Article  CAS  PubMed  Google Scholar 

  93. Gessner A, Waicz R, Lieske A, Paulke BR, Mäder K, Müller RH. Nanoparticles with decreasing surface hydrophobicities: influence on plasma protein adsorption. Int J Pharm. 2000;196:245–9.

    Article  CAS  PubMed  Google Scholar 

  94. Nguyen VH, Lee BJ. Protein corona: a new approach for nanomedicine design. Int J Nanomedicine. 2017;12:3137–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sempf K, Arrey T, Gelperina S, Schorge T, Meyer B, Karas M, et al. Adsorption of plasma proteins on uncoated PLGA nanoparticles. Eur J Pharm Biopharm. 2013;85:53–60.

    Article  CAS  PubMed  Google Scholar 

  96. Vogt C, Pernemalm M, Kohonen P, Laurent S, Hultenby K, Vahter M, et al. Proteomics analysis reveals distinct corona composition on magnetic nanoparticles with different surface coatings: implications for interactions with primary human macrophages. PLoS One. 2015;10:1–20.

    Google Scholar 

  97. Walkey CD, Chan WCW. Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem Soc Rev. 2012;41:2780–99.

    Article  CAS  PubMed  Google Scholar 

  98. Partikel K, Korte R, Mulac D, Humpf H, Langer K. Beilstein J Nanotechnol. 2019;10:1002–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rai R, Alwani S, Badea I. Polymeric nanoparticles in gene therapy: new avenues of design and optimization for delivery applications. Polymers (Basel). 2019;11:E745.

    Article  CAS  Google Scholar 

  100. Blunk T, Hochstrasser DF, Sanchez J-C, Müller BW, Müller RH. Colloidal carriers for intravenous drug targeting: plasma protein adsorption patterns on surface-modified latex particles evaluated by two-dimensional polyacrylamide gel electrophoresis. Electrophoresis. 1993;14:1382–7.

    Article  CAS  PubMed  Google Scholar 

  101. Müller RH, Rühl D, Lück M, Paulke BR. Influence of fluorescent labelling of polystyrene particles on phagocytic uptake, surface hydrophobicity, and plasma protein adsorption. Pharm Res. 1997;14:18–24.

    Article  PubMed  Google Scholar 

  102. Zhang H, Wu T, Yu W, Ruan S, He Q, Gao H. Ligand size and conformation affect the behavior of nanoparticles coated with in vitro and in vivo protein corona. ACS Appl Mater Interfaces. 2018;10:9094–103.

    Article  CAS  PubMed  Google Scholar 

  103. Saha K, Rahimi M, Yazdani M, Kim ST, Moyano DF, Hou S, et al. Regulation of macrophage recognition through the interplay of nanoparticle surface functionality and protein corona. ACS Nano. 2016;10:4421–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mahmoudi M. Antibody orientation determines corona mistargeting capability. Nat Nanotechnol. 2018;13:775–6.

    Article  CAS  PubMed  Google Scholar 

  105. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov DR, et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol. 2013;8:137–43.

    Article  CAS  PubMed  Google Scholar 

  106. Leroux J, Gravel P, Balant L, Volet B, Anner BM, Allémann E, et al. Internalization of poly(D,L-lactic acid) nanoparticles by isolated human leukocytes and analysis of plasma proteins adsorbed onto the particles. J Biomed Mater Res. 1994;28:471–81.

    Article  CAS  PubMed  Google Scholar 

  107. Bertrand N, Grenier P, Mahmoudi M, Lima EM, Appel EA, Dormont F, et al. Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nat Commun. 2017;8:1–8.

    Article  CAS  Google Scholar 

  108. Samaridou E, Kalamidas N, Santalices I, Crecente-Campo J, Alonso MJ. Tuning the PEG surface density of the PEG-PGA enveloped octaarginine-peptide nanocomplexes. Drug Deliv Transl Res. 2020;10:241–58.

    Article  PubMed  Google Scholar 

  109. Samadi N, Van Steenbergen MJ, Van Den Dikkenberg JB, Vermonden T, Van Nostrum CF, Amidi M, et al. Nanoparticles based on a hydrophilic polyester with a sheddable peg coating for protein delivery. Pharm Res. 2014;31:2593–604.

    Article  CAS  PubMed  Google Scholar 

  110. Zhu X, Tao W, Liu D, Wu J, Guo Z, Ji X, et al. Surface de-PEGylation controls nanoparticle-mediated siRNA delivery in vitro and in vivo. Theranostics. 2017;7:1990–2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sanchez L, Yi Y, Yu Y. Effect of partial PEGylation on particle uptake by macrophages. Nanoscale. 2017;9:288–97.

    Article  CAS  PubMed  Google Scholar 

  112. Grenier P, de Viana IMO, Lima EM, Bertrand N. Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo. J Control Release. 2018;287:121–31.

    Article  CAS  PubMed  Google Scholar 

  113. Almeida M, Magalhães M, Veiga F, Figueiras A Poloxamers, poloxamines and polymeric micelles: definition, structure and therapeutic applications in cancer. J Polym Res. 2018;25.

  114. Neal JC, Stolnik S, Schacht E, Kenawy ER, Garnett MC, Davis SS, et al. In vitro displacement by rat serum of adsorbed radiolabeled poloxamer and poloxamine copolymers from model and biodegradable nanospheres. J Pharm Sci. 1998;87:1242–8.

    Article  CAS  PubMed  Google Scholar 

  115. Stolnik S, Daudali B, Arien A, Whetstone J, Heald CR, Garnett MC, et al. The effect of surface coverage and conformation of poly (ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers. Biochim Biophys Acta Biomembr. 2001;1514:261–79.

    Article  CAS  Google Scholar 

  116. Kreuter J. Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. J Nanosci Nanotechnol. 2004;4:484–8.

    Article  CAS  PubMed  Google Scholar 

  117. Elsabahy M, Zhang S, Zhang F, Deng ZJ, Lim YH, Wang H, et al. Surface charges and shell crosslinks each play significant roles in mediating degradation, biofouling, cytotoxicity and immunotoxicity for polyphosphoester-based nanoparticles. Sci Rep. 2013;3:3313.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zhao Z, Wang J, Mao HQ, Leong KW. Polyphosphoesters in drug and gene delivery. Adv Drug Deliv Rev. 2003;55:483–99.

    Article  CAS  PubMed  Google Scholar 

  119. Simon J, Wolf T, Klein K, Landfester K, Wurm FR, Mailänder V. Hydrophilicity regulates the stealth properties of polyphosphoester-coated nanocarriers. Angew Chem Int Ed Eng. 2018;57:5548–53.

    Article  CAS  Google Scholar 

  120. Krug LM, Ragupathi G, Ng KK, Hood C, Jennings HJ, Guo Z, et al. Vaccination of small cell lung cancer patients with polysialic acid or N-propionylated polysialic acid conjugated to keyhole limpet hemocyanin. Clin Cancer Res. 2004;10:916–23.

    Article  CAS  PubMed  Google Scholar 

  121. Tiede A, Allen G, Bauer A, Chowdary P, Collins P, Goldstein B, et al. SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): first-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A. Haemophilia. 2020;26:47–55.

    Article  CAS  PubMed  Google Scholar 

  122. Shimoda A, Tahara Y, Sawada S i, Sasaki Y, Akiyoshi K. Glycan profiling analysis using evanescent-field fluorescence-assisted lectin array: importance of sugar recognition for cellular uptake of exosomes from mesenchymal stem cells. Biochem Biophys Res Commun. 2017;491:701–7.

    Article  CAS  PubMed  Google Scholar 

  123. Spence S, Greene MK, Fay F, Hams E, Saunders SP, Hamid U, et al. Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation. Sci Transl Med. 2015;7:1–13.

    Article  CAS  Google Scholar 

  124. Vasvani S, Kulkarni P, Rawtani D Hyaluronic acid: a review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. Int J Biol Macromol. 2019.

  125. Cadete A, Alonso MJ. Targeting cancer with hyaluronic acid-based nanocarriers: recent advances and translational perspectives. Nanomedicine. 2016;11:2341–57.

    Article  CAS  PubMed  Google Scholar 

  126. García KP, Zarschler K, Barbaro L, Barreto JA, O’Malley W, Spiccia L, et al. Zwitterionic-coated “stealth” nanoparticles for biomedical applications: recent advances in countering biomolecular corona formation and uptake by the mononuclear phagocyte system. Small. 2014;10:2516–29.

    Article  CAS  Google Scholar 

  127. Sobczynski DJ, Eniola-Adefeso O. IgA and IgM protein primarily drive plasma corona-induced adhesion reduction of PLGA nanoparticles in human blood flow. Bioeng Transl Med. 2017;2:180–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mahmoudi M. Debugging nano–bio interfaces: systematic strategies to accelerate clinical translation of nanotechnologies. Trends Biotechnol. 2018;36:755–69.

    Article  CAS  PubMed  Google Scholar 

  129. Hajipour MJ, Laurent S, Aghaie A, Rezaee F, Mahmoudi M. Personalized protein coronas: a “key” factor at the nanobiointerface. Biomater Sci. 2014;2:1210.

    Article  CAS  PubMed  Google Scholar 

  130. Braun NJ, DeBrosse MC, Hussain SM, Comfort KK. Modification of the protein corona–nanoparticle complex by physiological factors. Mater Sci Eng C Mater Biol Appl. 2016;64:34–42.

    Article  CAS  PubMed  Google Scholar 

  131. Jayaram DT, Pustulka SM, Mannino RG, Lam WA, Payne CK. Protein corona in response to flow: effect on protein concentration and structure. Biophys J. 2018;115:209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Coty J-B, Vauthier C. Characterization of nanomedicines: a reflection on a field under construction needed for clinical translation success. J Control Release. 2018;275:254–68.

    Article  CAS  PubMed  Google Scholar 

  133. Müller LK, Simon J, Rosenauer C, Mailänder V, Morsbach S, Landfester K. The transferability from animal models to humans: challenges regarding aggregation and protein corona formation of nanoparticles. Biomacromolecules. 2018;19:374–85.

    Article  PubMed  CAS  Google Scholar 

  134. Sobczynski DJ, Eniola-Adefeso O. Effect of anticoagulants on the protein corona-induced reduced drug carrier adhesion efficiency in human blood flow. Acta Biomater. 2017;48:186–94.

    Article  CAS  PubMed  Google Scholar 

  135. Salvador-Morales C, Zhang L, Langer R, Farokhzad OC. Immunocompatibility properties of lipid–polymer hybrid nanoparticles with heterogeneous surface functional groups. Biomaterials. 2009;30:2231–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Docter D, Distler U, Storck W, Kuharev J, Wünsch D, Hahlbrock A, et al. Quantitative profiling of the protein coronas that form around nanoparticles. Nat Protoc. 2014;9:2030–44.

    Article  CAS  PubMed  Google Scholar 

  137. Chen D, Ganesh S, Wang W, Amiji M. The role of surface chemistry in serum protein corona-mediated cellular delivery and gene silencing with lipid nanoparticles. Nanoscale. 2019;11:8760–75.

    Article  CAS  PubMed  Google Scholar 

  138. Palchetti S, Pozzi D, Capriotti AL, La Barbera G, Chiozzi RZ, Digiacomo L, et al. Influence of dynamic flow environment on nanoparticle-protein corona: from protein patterns to uptake in cancer cells. Colloids Surf B: Biointerfaces. 2017;153:263–71.

    Article  CAS  PubMed  Google Scholar 

  139. Capriotti AL, Cavaliere C, Piovesana S. Liposome protein corona characterization as a new approach in nanomedicine. Anal Bioanal Chem. 2019;411:4313–26.

    Article  CAS  PubMed  Google Scholar 

  140. Arvizo RR, Giri K, Moyano D, Miranda OR, Madden B, McCormick DJ, et al. Identifying new therapeutic targets via modulation of protein corona formation by engineered nanoparticles. PLoS One. 2012;7:1–8.

    Article  CAS  Google Scholar 

  141. Walkey CD, Olsen JB, Song F, Liu R, Guo XH, Olsen DWH, et al. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano. 2014;8:2439–55.

    Article  CAS  PubMed  Google Scholar 

  142. Frost R, Langhammer C, Cedervall T. Real-time in situ analysis of biocorona formation and evolution on silica nanoparticles in defined and complex biological environments. Nanoscale. 2017;9:3620–8.

    Article  CAS  PubMed  Google Scholar 

  143. Capriotti AL, Caracciolo G, Caruso G, Cavaliere C, Pozzi D, Samperi R, et al. Analysis of plasma protein adsorption onto DC-Chol-DOPE cationic liposomes by HPLC-CHIP coupled to a Q-TOF mass spectrometer. Anal Bioanal Chem. 2010;398:2895–903.

    Article  CAS  PubMed  Google Scholar 

  144. Weber C, Morsbach S, Landfester K. Possibilities and limitations of different separation techniques for the analysis of the protein corona. Angew Chem Int Ed Eng. 2019;58:12787–94.

    Article  CAS  Google Scholar 

  145. Wang Y, Olesik SV. Separation of PEGylated gold nanoparticles by micellar enhanced electrospun fiber based ultrathin layer chromatography. Anal Chem. 2018;90:2662–70.

    Article  CAS  PubMed  Google Scholar 

  146. Chetwynd A, Guggenheim E, Briffa S, Thorn J, Lynch I, Valsami-Jones E. Current application of capillary electrophoresis in nanomaterial characterisation and its potential to characterise the protein and small molecule corona. Nanomaterials. 2018;8:99.

    Article  PubMed Central  CAS  Google Scholar 

  147. García-Álvarez R, Hadjidemetriou M, Sánchez-Iglesias A, Liz-Marzán LM, Kostarelos K. In vivo formation of protein corona on gold nanoparticles. The effect of their size and shape. Nanoscale. 2018;10:1256–64.

    Article  PubMed  Google Scholar 

  148. Liu W, Rose J, Plantevin S, Auffan M, Bottero J-Y, Vidaud C. Protein corona formation for nanomaterials and proteins of a similar size: hard or soft corona? Nanoscale. 2013;5:1658.

    Article  CAS  PubMed  Google Scholar 

  149. Pederzoli F, Tosi G, Vandelli MA, Belletti D, Forni F, Ruozi B. Protein corona and nanoparticles: how can we investigate on? Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017;9:e1467.

    Article  CAS  Google Scholar 

  150. Contado C. Field flow fractionation techniques to explore the “nano-world”. Anal Bioanal Chem. 2017;409:2501–18.

    Article  CAS  PubMed  Google Scholar 

  151. Maiolo D, Bergese P, Mahon E, Dawson KA, Monopoli MP. Surfactant titration of nanoparticle–protein corona. Anal Chem. 2014;86:12055–63.

    Article  CAS  PubMed  Google Scholar 

  152. Zhang H, Peng J, Li X, Liu S, Hu Z, Xu G, et al. A nano-bio interfacial protein corona on silica nanoparticle. Colloids Surf B: Biointerfaces. 2018;167:220–8.

    Article  CAS  PubMed  Google Scholar 

  153. Rabilloud T, Lelong C. Two-dimensional gel electrophoresis in proteomics: a tutorial. J Proteome. 2011;74:1829–41.

    Article  CAS  Google Scholar 

  154. Karpievitch YV, Polpitiya AD, Anderson GA, Smith RD, Dabney AR. Liquid chromatography mass spectrometry-based proteomics: biological and technological aspects. Ann Appl Stat. 2011;4:1797–823.

    Article  Google Scholar 

  155. Galmarini S, Hanusch U, Giraud M, Cayla N, Chiappe D, von Moos N, et al. Beyond unpredictability: the importance of reproducibility in understanding the protein corona of nanoparticles. Bioconjug Chem. 2018;29:3385–93.

    Article  CAS  PubMed  Google Scholar 

  156. Hadjidemetriou M, Al-Ahmady Z, Kostarelos K. Time-evolution of in vivo protein corona onto blood-circulating PEGylated liposomal doxorubicin (DOXIL) nanoparticles. Nanoscale. 2016;8:6948–57.

    Article  CAS  PubMed  Google Scholar 

  157. Corbo C, Molinaro R, Taraballi F, Toledano Furman NE, Hartman KA, Sherman MB, et al. Unveiling the in vivo protein corona of circulating leukocyte-like carriers. ACS Nano. 2017;11:3262–73.

    Article  CAS  PubMed  Google Scholar 

  158. Amici A, Caracciolo G, Digiacomo L, Gambini V, Marchini C, Tilio M, et al. In vivo protein corona patterns of lipid nanoparticles. RSC Adv. 2017;7:1137–45.

    Article  CAS  Google Scholar 

  159. Hadjidemetriou M, McAdam S, Garner G, Thackeray C, Knight D, Smith D, et al. The human in vivo biomolecule corona onto PEGylated liposomes: a proof-of-concept clinical study. Adv Mater. 2019;31:1–9.

    Google Scholar 

  160. Papi M, Palmieri V, Palchetti S, Pozzi D, Digiacomo L, Guadagno E, et al. Exploitation of nanoparticle-protein interactions for early disease detection. Appl Phys Lett. 2019;114:163702.

    Article  CAS  Google Scholar 

  161. Hadjidemetriou M, Al-ahmady Z, Buggio M, Swift J, Kostarelos K. A novel scavenging tool for cancer biomarker discovery based on the blood-circulating nanoparticle protein corona. Biomaterials. 2019;188:118–29.

    Article  CAS  PubMed  Google Scholar 

  162. Palchetti S, Pozzi D, Mahmoudi M, Caracciolo G. Exploitation of nanoparticle–protein corona for emerging therapeutic and diagnostic applications. J Mater Chem B. 2016;4:4376–81.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work has been done within the 2-INTRATARGET project (PCIN-2017-129/ AEI) funded by MINECO-PCIN-2017-129/ AEI, under the frame of EuroNanoMed III, by FEDER/ Spanish Ministry of Science, Innovation and Universities (ref.: SAF2017-86634-R) and by Xunta de Galicia, Consellería de Educación e Ordenación Universitaria (Grupos de Referencia Competitiva, ED431C 2017/09). G. Berrecoso acknowledges the financial support by the Xunta de Galicia (ED481A-2018/047) through the “axudas de apoio á etapa predoutoral 2018” grant.

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  1. Center for Research in Molecular Medicine and Chronic Diseases, 15782, Santiago de Compostela, Spain

    Germán Berrecoso, José Crecente-Campo & María José Alonso

  2. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), IDIS Research Institute, 15706, Santiago de Compostela, Spain

    Germán Berrecoso, José Crecente-Campo & María José Alonso

  3. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Germán Berrecoso, José Crecente-Campo & María José Alonso

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  1. Germán Berrecoso
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Correspondence to José Crecente-Campo or María José Alonso.

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Berrecoso, G., Crecente-Campo, J. & Alonso, M.J. Unveiling the pitfalls of the protein corona of polymeric drug nanocarriers. Drug Deliv. and Transl. Res. 10, 730–750 (2020). https://doi.org/10.1007/s13346-020-00745-0

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