DOI

  • Stefaan De Koker
  • Federico Perche
  • Kim Deswarte
  • Virginie Malard
  • Hamida Hammad
  • Patrick Baril
  • Thierry Benvegnu
  • Paul-Alain Jaffrès
  • Sander A A Kooijmans
  • Raymond Schiffelers
  • Stefan Lienenklaus
  • Patrick Midoux
  • Chantal Pichon

In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.

Original languageEnglish
Pages (from-to)9815-9829
Number of pages15
JournalACS Nano
Volume12
Issue number10
DOIs
Publication statusPublished - 1 Oct 2018

    Research areas

  • cancer therapy, lipopolyplexes, modified nucleosides, mRNA, T cell, type I interferon

ID: 40493019