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Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide

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Abstract
To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.
Keywords
DELIVERY, VACCINES, PSEUDOURIDINE, VACCINATION, ACTIVATION, RESPONSES, THERAPY, MESSAGE, CD8+T cell responses, cpp, endosomal escape, mRNA vaccines, RALA mRNA, nanocomplexes

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MLA
Udhayakumar, Vimal Kumar et al. “Arginine-rich Peptide-based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide.” ADVANCED HEALTHCARE MATERIALS 6.13 (2017): n. pag. Print.
APA
Udhayakumar, V. K., De Beuckelaer, A., McCaffrey, J., McCrudden, C. M., Kirschman, J. L., Vanover, D., Van Hoecke, L., et al. (2017). Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide. ADVANCED HEALTHCARE MATERIALS, 6(13).
Chicago author-date
Udhayakumar, Vimal Kumar, Ans De Beuckelaer, Joanne McCaffrey, Cian M McCrudden, Jonathan L Kirschman, Daryll Vanover, Lien Van Hoecke, et al. 2017. “Arginine-rich Peptide-based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide.” Advanced Healthcare Materials 6 (13).
Chicago author-date (all authors)
Udhayakumar, Vimal Kumar, Ans De Beuckelaer, Joanne McCaffrey, Cian M McCrudden, Jonathan L Kirschman, Daryll Vanover, Lien Van Hoecke, Kenny Roose, Kim Deswarte, Bruno De Geest, Stefan Lienenklaus, Philip J Santangelo, Johan Grooten, Helen O McCarthy, and Stefaan De Koker. 2017. “Arginine-rich Peptide-based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide.” Advanced Healthcare Materials 6 (13).
Vancouver
1.
Udhayakumar VK, De Beuckelaer A, McCaffrey J, McCrudden CM, Kirschman JL, Vanover D, et al. Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide. ADVANCED HEALTHCARE MATERIALS. 2017;6(13).
IEEE
[1]
V. K. Udhayakumar et al., “Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide,” ADVANCED HEALTHCARE MATERIALS, vol. 6, no. 13, 2017.
@article{8527478,
  abstract     = {To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.},
  articleno    = {1601412},
  author       = {Udhayakumar, Vimal Kumar and De Beuckelaer, Ans and McCaffrey, Joanne and McCrudden, Cian M and Kirschman, Jonathan L and Vanover, Daryll and Van Hoecke, Lien and Roose, Kenny and Deswarte, Kim and De Geest, Bruno and Lienenklaus, Stefan and Santangelo, Philip J and Grooten, Johan and McCarthy, Helen O and De Koker, Stefaan},
  issn         = {2192-2640},
  journal      = {ADVANCED HEALTHCARE MATERIALS},
  keywords     = {DELIVERY,VACCINES,PSEUDOURIDINE,VACCINATION,ACTIVATION,RESPONSES,THERAPY,MESSAGE,CD8+T cell responses,cpp,endosomal escape,mRNA vaccines,RALA mRNA,nanocomplexes},
  language     = {eng},
  number       = {13},
  pages        = {13},
  title        = {Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide},
  url          = {http://dx.doi.org/10.1002/adhm.201601412},
  volume       = {6},
  year         = {2017},
}

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