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

Kevin Van der Jeught, Stefaan De Koker, Lukasz Bialkowski, Carlo Heirman, Patrick Tjok Joe, Federico Perche, Sarah Maenhout, Sanne Bevers, Katrijn Broos, Kim Deswarte, Virginie Malard, Hamida Hammad, Patrick Baril, Thierry Benvegnu, Paul-Alain Jaffrès, Sander A A Kooijmans, Raymond Schiffelers, Stefan Lienenklaus, Patrick Midoux, Chantal PichonKarine Breckpot, Kris Thielemans

Onderzoeksoutput: Article

31 Citaten (Scopus)
36 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)9815-9829
Aantal pagina's15
TijdschriftACS Nano
Volume12
Nummer van het tijdschrift10
DOI's
StatusPublished - 1 okt 2018

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