Even though it is known for more than one decade that antigen-encoding RNA can deliver antigenic information to induce antigen-specific immunity against cancer, the nature and mechanism of RNA uptake have remained enigmatic. In this study, we investigated the pharmacokinetics of naked RNA administered into the lymph node. We observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs). Furthermore, in vitro and in vivo studies revealed that the efficient internalization of RNA by human and murine DCs is primarily driven by macropinocytosis. Selective inhibition of macropinocytosis by compounds or as a consequence of DC maturation abrogated RNA internalization and delivery of encoded antigens. Our findings imply that bioavailability of recombinant RNA vaccines in vivo highly depends on the density and the maturation stage of DCs at the administration site and are of importance for the design of RNA-based clinical immunotherapy protocols.
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We thank Marc Holzmann for excellent assistance. This work was supported by the Combined Project Grant SFB 432 and by the GO-Bio funding of the Federal Ministry of Education and Research (BMBF).
U Sahin (co-founder, chief executive officer), C Huber (co-founder) and CM Britten (employee) are associated with Ribological, BioNTech AG (Mainz, Germany), a company, which develops RNA-based cancer vaccines. U Sahin, S Kreiter, Ö Tureci and A Selmi are inventors on a patent application, in which parts of this paper are covered.
Supplementary Information accompanies the paper on Gene Therapy website
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Diken, M., Kreiter, S., Selmi, A. et al. Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. Gene Ther 18, 702–708 (2011). https://doi.org/10.1038/gt.2011.17
- dendritic cells
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