期刊
ACS NANO
卷 12, 期 10, 页码 9815-9829出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b00966
关键词
mRNA; lipopolyplexes; type I interferon; cancer therapy; T cell; modified nucleosides
类别
资金
- Interuniversity Attraction Poles Program-Belgian State-Belgian Science Policy
- National Cancer Plan of the Federal Ministry of Health
- Stichting tegen Kanker
- Vlaamse Liga tegen Kanker
- EU FP7
- IWT-TBM program
- FWO-Vlaanderen
- Fonds Germaine Eisendrath-Dubois
- Scientific Fund Willy Gepts of the University Hospital Brussels
- IWT
- eTheRNA Immunotherapies
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.
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