Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Nature Biotechnology volume 25, pages 1159–1164 (2007)Cite this article

Abstract

Antigen targeting1,2,3,4,5 and adjuvancy schemes6,7 that respectively facilitate delivery of antigen to dendritic cells and elicit their activation have been explored in vaccine development. Here we investigate whether nanoparticles can be used as a vaccine platform by targeting lymph node–residing dendritic cells via interstitial flow and activating these cells by in situ complement activation. After intradermal injection, interstitial flow transported ultra-small nanoparticles (25 nm) highly efficiently into lymphatic capillaries and their draining lymph nodes, targeting half of the lymph node–residing dendritic cells, whereas 100-nm nanoparticles were only 10% as efficient. The surface chemistry of these nanoparticles activated the complement cascade, generating a danger signal in situ and potently activating dendritic cells. Using nanoparticles conjugated to the model antigen ovalbumin, we demonstrate generation of humoral and cellular immunity in mice in a size- and complement-dependent manner.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ultra-small nanoparticles accumulate in lymph nodes after intradermal injection, whereas slightly larger ones do not.
Figure 2: Polyhydroxylated nanoparticle surfaces activate complement.
Figure 3: Lymph node-targeting, complement-activating nanoparticles induce dendritic cell maturation in vivo.
Figure 4: Lymph node–targeting, complement-activating nanoparticles induce antigen-specific adaptive immune responses.

Similar content being viewed by others

References

  1. Bonifaz, L.C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).

    Article  CAS  Google Scholar 

  2. Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).

    Article  CAS  Google Scholar 

  3. Kwon, Y.J., James, E., Shastri, N. & Frechet, J.M. In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles. Proc. Natl. Acad. Sci. USA 102, 18264–18268 (2005).

    Article  CAS  Google Scholar 

  4. Trumpfheller, C. et al. Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. J. Exp. Med. 203, 607–617 (2006).

    Article  CAS  Google Scholar 

  5. Wang, C. et al. Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines. Nat. Mater. 3, 190–196 (2004).

    Article  CAS  Google Scholar 

  6. O'Hagan, D.T. & Valiante, N.M. Recent advances in the discovery and delivery of vaccine adjuvants. Nat. Rev. Drug Discov. 2, 727–735 (2003).

    Article  CAS  Google Scholar 

  7. Ulevitch, R.J. Therapeutics targeting the innate immune system. Nat. Rev. Immunol. 4, 512–520 (2004).

    Article  CAS  Google Scholar 

  8. Rehor, A., Hubbell, J.A. & Tirelli, N. Oxidation-sensitive polymeric nanoparticles. Langmuir 21, 411–417 (2005).

    Article  CAS  Google Scholar 

  9. Wilson, N.S. et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102, 2187–2194 (2003).

    Article  CAS  Google Scholar 

  10. Reddy, S.T., Swartz, M.A. & Hubbell, J.A. Targeting dendritic cells with biomaterials: developing the next generation of vaccines. Trends Immunol. 27, 573–579 (2006).

    Article  CAS  Google Scholar 

  11. Randolph, G.J., Angeli, V. & Swartz, M.A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5, 617–628 (2005).

    Article  CAS  Google Scholar 

  12. Pack, D.W. Timing is everything. Nat. Mater. 3, 133–134 (2004).

    Article  CAS  Google Scholar 

  13. Little, S.R. et al. Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines. Proc. Natl. Acad. Sci. USA 101, 9534–9539 (2004).

    Article  CAS  Google Scholar 

  14. Storni, T. et al. Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J. Immunol. 172, 1777–1785 (2004).

    Article  CAS  Google Scholar 

  15. Fifis, T. et al. Size-dependent immunogenicity: therapeutic and protective properties of nano-vaccines against tumors. J. Immunol. 173, 3148–3154 (2004).

    Article  CAS  Google Scholar 

  16. van Broekhoven, C.L., Parish, C.R., Demangel, C., Britton, W.J. & Altin, J.G. Targeting dendritic cells with antigen-containing liposomes: a highly effective procedure for induction of antitumor immunity and for tumor immunotherapy. Cancer Res. 64, 4357–4365 (2004).

    Article  CAS  Google Scholar 

  17. Swartz, M.A. The physiology of the lymphatic system. Adv. Drug Deliv. Rev. 50, 3–20 (2001).

    Article  CAS  Google Scholar 

  18. Swartz, M.A. & Fleury, M.E. Interstitial flow and its effects in soft tissues. Annu. Rev. Biomed. Eng. 9, 229–256 (2007).

    Article  CAS  Google Scholar 

  19. Reddy, S.T., Rehor, A., Schmoekel, H.G., Hubbell, J.A. & Swartz, M.A. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J. Control. Release 112, 26–34 (2006).

    Article  CAS  Google Scholar 

  20. Nishioka, Y. & Yoshino, H. Lymphatic targeting with nanoparticulate system. Adv. Drug Deliv. Rev. 47, 55–64 (2001).

    Article  CAS  Google Scholar 

  21. Reddy, S.T., Berk, D.A., Jain, R.K. & Swartz, M.A. A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles. J. Appl. Physiol. 101, 1162–1169 (2006).

    Article  CAS  Google Scholar 

  22. Boscardin, S.B. et al. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses. J. Exp. Med. 203, 599–606 (2006).

    Article  CAS  Google Scholar 

  23. Carroll, M.C. The complement system in regulation of adaptive immunity. Nat. Immunol. 5, 981–986 (2004).

    Article  CAS  Google Scholar 

  24. Dempsey, P.W., Allison, M.E., Akkaraju, S., Goodnow, C.C. & Fearon, D.T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).

    Article  CAS  Google Scholar 

  25. Kemper, C. & Atkinson, J.P. T-cell regulation: with complements from innate immunity. Nat. Rev. Immunol. 7, 9–18 (2007).

    Article  CAS  Google Scholar 

  26. Kopf, M., Abel, B., Gallimore, A., Carroll, M. & Bachmann, M.F. Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat. Med. 8, 373–378 (2002).

    Article  CAS  Google Scholar 

  27. Gadjeva, M. et al. The covalent binding reaction of complement component C3. J. Immunol. 161, 985–990 (1998).

    CAS  PubMed  Google Scholar 

  28. Tang, L., Liu, L. & Elwing, H.B. Complement activation and inflammation triggered by model biomaterial surfaces. J. Biomed. Mater. Res. 41, 333–340 (1998).

    Article  CAS  Google Scholar 

  29. Nilsson, B., Ekdahl, K.N., Mollnes, T.E. & Lambris, J.D. The role of complement in biomaterial-induced inflammation. Mol. Immunol. 44, 82–94 (2007).

    Article  CAS  Google Scholar 

  30. Kidane, A. & Park, K. Complement activation by PEO-grafted glass surfaces. J. Biomed. Mater. Res. 48, 640–647 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Pasquier, V. Borel, V. Garea for valuable technical assistance; J.M. Rutkowski for scientific discussions; J.B. Dixon for MATLAB programming. Project funded by the Competence Centre for Materials Science and Technology (CCMX) of the ETH-Board, Switzerland (to M.A.S. and J.A.H.).

Author information

Author notes

  1. Veronique Angeli

    Present address: Present address: Department of Microbiology, Immunology Programme, National University of Singapore, Singapore 117456.,

Authors and Affiliations

  1. Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland

    Sai T Reddy, André J van der Vlies, Eleonora Simeoni, Conlin P O'Neil, Leslie K Lee, Melody A Swartz & Jeffrey A Hubbell

  2. Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Veronique Angeli & Gwendalyn J Randolph

  3. Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland

    Melody A Swartz & Jeffrey A Hubbell

Authors
  1. Sai T Reddy
    View author publications

    Search author on:PubMed Google Scholar

  2. André J van der Vlies
    View author publications

    Search author on:PubMed Google Scholar

  3. Eleonora Simeoni
    View author publications

    Search author on:PubMed Google Scholar

  4. Veronique Angeli
    View author publications

    Search author on:PubMed Google Scholar

  5. Gwendalyn J Randolph
    View author publications

    Search author on:PubMed Google Scholar

  6. Conlin P O'Neil
    View author publications

    Search author on:PubMed Google Scholar

  7. Leslie K Lee
    View author publications

    Search author on:PubMed Google Scholar

  8. Melody A Swartz
    View author publications

    Search author on:PubMed Google Scholar

  9. Jeffrey A Hubbell
    View author publications

    Search author on:PubMed Google Scholar

Contributions

S.T.R. designed and performed the research, analyzed the data and wrote the manuscript; A.J.v.d.V. synthesized materials and analyzed synthetic data; E.S. developed methods on T-cell activation and analyzed the data; V.A. performed the research on T-cell adoptive transfer, analyzed the data and provided useful discussion on interpretation; G.J.R. analyzed the data and provided useful discussion on interpretation; C.P.O. synthesized materials and analyzed synthetic data; L.K.L. developed methods on T-cell activation and antibody titer measurement; M.A.S. designed the research, analyzed the data and wrote the manuscript; J.A.H. designed the research, analyzed the data and wrote the manuscript.

Corresponding authors

Correspondence to Melody A Swartz or Jeffrey A Hubbell.

Ethics declarations

Competing interests

The Ecole Polytechnique Fédérale de Lausanne has filed a patent application on technology related to this manuscript, and S.T.R., A.J.v.d.V, M.A.S. and J.A.H. are named as inventors on this application.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4; Supplementary Methods (PDF 428 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reddy, S., van der Vlies, A., Simeoni, E. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25, 1159–1164 (2007). https://doi.org/10.1038/nbt1332

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nbt1332

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing