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ACS Nano. 2018 Oct 23;12(10):9815-9829. doi: 10.1021/acsnano.8b00966. Epub 2018 Oct 1.

Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-Cell Immunity with Improved Inflammatory Safety.

Author information

1
Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences , Vrije Universiteit Brussel (VUB) , Brussels 1090 , Belgium.
2
eTheRNA Immunotherapies NV , Niel 2845 , Belgium.
3
Centre de Biophysique Moléculaire, CNRS UPR 4301, University and Inserm , Orléans 45071 , France.
4
VIB Inflammation Research Center , UGent , Ghent 9052 , Belgium.
5
Ecole Nationale Supérieure de Chimie de Rennes, CNRS UMR6226 , Rennes 35708 , France.
6
CEMA, CNRS UMR 6521, SFR148 ScInBioS , Université de Brest , Brest 29238 , France.
7
University Medical Center Utrecht, Universiteit Utrecht , Utrecht 3584 , Netherlands.
8
Hannover Medical School , Hannover 30625 , Germany.

Abstract

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.

KEYWORDS:

T cell; cancer therapy; lipopolyplexes; mRNA; modified nucleosides; type I interferon

PMID:
30256609
DOI:
10.1021/acsnano.8b00966
[Indexed for MEDLINE]
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