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Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses1. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated2. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA3,4, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

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  • 07 June 2016

    The competing financial interests statement did not display correctly online when this paper was first published; this has been corrected and the statement is now available.


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The authors thank M. Holzmann, R. Roth, U. Schmitt, M. Brkic, A. König, C. Worm, N. Krimmel, A.-K. Thiel, C. Bender, M. Suchan, A.-L. Popa, P. Bezerra Gomes, S. Herbert, M. Lux, D. Wintergerst, V. Bischoff, R. Krishna, Y. Hajime, J. Groß, A. Spruss, M. Erdeljan, S. Wöll, T. Bukur, H. Muramatsu and M. Baiersdörfer for technical support, NIH Tetramer Core Facility for providing gp70 MHC class I tetramer, A. Kong for critical reading, A. Kemmer-Brück, D. Schwarck, S. Bolte for clinical operations support and K. Kariko for advice. This work was supported by the technology innovation program of the Rhineland Palatinate government, the InnoTop program, the CI3 Cutting Edge Cluster Funding of the German Ministry of Technology (BMBF) and the Collaborative Research Group 1066 of Deutsche Forschungsgemeinschaft (DFG). L.M.K. was funded by the Graduate School of Immunotherapy 1043 of DFG.

Author information

Author notes

    • Lena M. Kranz
    •  & Mustafa Diken

    These authors contributed equally to this work.

    • Özlem Türeci
    •  & Ugur Sahin

    These authors jointly supervised this work.


  1. TRON–Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany

    • Lena M. Kranz
    • , Mustafa Diken
    • , Sebastian Kreiter
    • , Fulvia Vascotto
    • , Abderraouf Selmi
    • , Richard Rae
    • , Sebastian Attig
    • , Christoph Huber
    •  & Ugur Sahin
  2. Research Center for Immunotherapy (FZI), University Medical Center at the Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany

    • Lena M. Kranz
    • , Christian Grunwitz
    • , Mathias Vormehr
    • , Abderraouf Selmi
    • , Sebastian Attig
    •  & Ugur Sahin
  3. Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany

    • Mustafa Diken
    • , Heinrich Haas
    • , Sebastian Kreiter
    • , Kerstin C. Reuter
    • , Martin Meng
    • , Daniel Fritz
    • , Hossam Hefesha
    • , Christian Grunwitz
    • , Mathias Vormehr
    • , Yves Hüsemann
    • , Andreas N. Kuhn
    • , Janina Buck
    • , Evelyna Derhovanessian
    • , Jan Diekmann
    • , Robert A. Jabulowsky
    • , Sandra Heesch
    • , Christoph Huber
    •  & Ugur Sahin
  4. Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany

    • Carmen Loquai
    •  & Stephan Grabbe
  5. Department of Dermatology, Heidelberg University Hospital, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany

    • Jessica Hassel
  6. Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Germany, Langenbeckstr. 1, Mainz 55131, Germany

    • Peter Langguth
  7. Cluster for Individualized Immune Intervention, Kupferbergterasse 19, Mainz 55116, Germany

    • Özlem Türeci


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U.S. was responsible for conception and experimental strategy of the study. Formulation development was performed by H.H. and P.L. Design and analysis of the experiments were done by L.M.K, M.D., H.H., S.K, M.M. and D.F. supported by K.C.R. and F.V. L.M.K, M.D., M.M., D.F., K.C.R., A.S., F.V., Y.H., Ho.He, C.G. and M.V. performed the experiments and acquired the data. C.L., J. H., J.D., A.N.K., J.B., R.J., S.H., S.G., E.D., R.R. and S.A. were involved in design, implementation or laboratory analyses of the clinical study. L.M.K., M.D., Ö.T. and U.S. interpreted the data and drafted the manuscript. C.H. supported the revision of the manuscript.

Competing interests

U.S., H.H, M.M., D.F., K.C.R, C.G., Ho.He, Y.H., M.V., A.N.K., J.B., E.D., J.D., R.J. and S.H. are employees at BioNTech AG (Mainz, Germany). M.D. and S.K. are working as consultants for BioNTech AG (Mainz, Germany). U.S., L.M.K., M.D., H.H., S.K., D.F., M.M. and K.C.R. are inventors on patents and patent applications related to this study. U.S. and C.H are stock owners, C.H. is advisor and supervisory board member and U.S. is management board member of BioNTech AG. All other authors have no potential conflict of interest.

Corresponding author

Correspondence to Ugur Sahin.

Reviewer Information: Nature thanks O. Farokhzad, C. G. Figdor, C. Melief, L. Zhang and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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