Article | Published:

Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo

Nature Nanotechnology volume 12, pages 387393 (2017) | Download Citation

Abstract

When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway. Serum and plasma proteins bound to the nanoworms are mostly intercalated into the nanoworm shell. We show that C3 covalently binds to these absorbed proteins rather than the dextran shell and the protein-bound C3 undergoes dynamic exchange in vitro. Surface-bound proteins accelerate the assembly of the complement components of the alternative pathway on the nanoworm surface. When nanoworms pre-coated with human plasma were injected into mice, C3 and other adsorbed proteins undergo rapid loss. Our results provide important insight into dynamics of protein adsorption and complement opsonization of nanomedicines.

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Acknowledgements

The study was funded by the University of Colorado Denver start-up funding and NIH 1R01EB022040 to D.S. F.C. was supported by the International Postdoctoral Exchange Fellowship Program (2013) from China Postdoctoral Council. Molecular modelling studies were conducted at the University of Colorado Computational Chemistry and Biology Core Facility, which is supported in part by NIH/NCATS Colorado CTSA grant no. UL1 TR001082. S.M.M. acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsråd), reference 09-065746, and Technology and Production, reference 12-126894.

Author information

Author notes

    • Fangfang Chen
    •  & Guankui Wang

    These authors contributed equally to this work

Affiliations

  1. Department of Gastrointestinal Surgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun, Jilin 130033, China

    • Fangfang Chen
  2. The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, USA

    • Fangfang Chen
    • , Guankui Wang
    • , James I. Griffin
    • , Barbara Brenneman
    •  & Dmitri Simberg
  3. Division of Rheumatology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, 1775 Aurora Court, Aurora, Colorado 80045, USA

    • Nirmal K. Banda
    •  & V. Michael Holers
  4. Computational Chemistry and Biology Core Facility, the Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Boulevard, Aurora, Colorado 80045, USA

    • Donald S. Backos
  5. Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen, DK-2100 Copenhagen, Denmark

    • LinPing Wu
    •  & Seyed Moein Moghimi
  6. NanoScience Centre, University of Copenhagen, DK-2100 Copenhagen, Denmark

    • Seyed Moein Moghimi
  7. School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, UK

    • Seyed Moein Moghimi

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Contributions

F.C., G.W., J.I.G., B.B. and L.W. performed the experiments. D.S.B. performed complement modelling. S.M.M., N.K.B., V.M.H. and D.S. analysed the data and edited the manuscript. N.K.B. and V.M.H. provided critical reagents. S.M.M. and D.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dmitri Simberg.

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DOI

https://doi.org/10.1038/nnano.2016.269