Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation
Mustafa Diken,Sebastian Kreiter,Abderraouf Selmi,Cedrik M. Britten,Christoph Huber,Özlem Türeci,Ugur Sahin +6 more
TLDR
It is observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs), implying 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.Abstract:
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.read more
Citations
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mRNA vaccines — a new era in vaccinology
TL;DR: A detailed overview of mRNA vaccines is provided and future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use are considered.
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TL;DR: This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.
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Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy
Lena M. Kranz,Mustafa Diken,Heinrich Haas,Sebastian Kreiter,Carmen Loquai,Kerstin C. Reuter,Martin Meng,Daniel Fritz,Fulvia Vascotto,Hossam Hefesha,Christian Grunwitz,Mathias Vormehr,Yves Hüsemann,Abderraouf Selmi,Andreas Kuhn,Janina Buck,Evelyna Derhovanessian,Richard Rae,Sebastian Attig,Jan Diekmann,Robert A. Jabulowsky,Sandra Heesch,Jessica C. Hassel,Peter Langguth,Stephan Grabbe,Christoph Huber,Özlem Türeci,Ugur Sahin +27 more
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TL;DR: The endocytic pathways are introduced, new technologies to confirm the specific endocytical pathways are presented and factors for pathway selection are discussed, which may provide new thoughts for the design of novel multifunctional nanomedicines.
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Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine.
TL;DR: An overview of the field`s understanding of how nanoparticle physicochemical properties affect cellular interactions is summarized, cellular internalization pathways are reviewed, and intracellular nanoparticle trafficking and kinetics are explored.
References
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