Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: restoring the immunogenicity of immunosilent mRNA
Open accessAbstract
This study reports on the design of mRNA and adjuvant-loaded lipid nanoparticles for therapeutic cancer vaccination. The use of nucleoside-modified mRNA has previously been shown to improve the translational capacity and safety of mRNA-therapeutics, as it prevents the induction of type I interferons (IFNs). However, type I IFNs were identified as the key molecules that trigger the activation of antigen presenting cells, and as such drive T cell immunity. We demonstrate that nucleoside-modified mRNA can be co-delivered with the clinically approved TLR agonist monophosphoryl lipid A (MPLA). As such, we simultaneously allow high antigen expression in vivo while substituting the type I IFN response by a more controllable adjuvant. This strategy shows promise to induce effective antigen-specific T cell immunity and may be useful to enhance the safety of mRNA vaccines.
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Several preclinical studies have indicated that an unmodified mRNA platform induces a more pronounced type-I IFN-polarized innate immune response.
“Several preclinical studies have indicated that an unmodified mRNA platform induces a more pronounced type-I IFN-polarized innate immune response [11,62]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [62]
Cationic mRNA LNPs composed of a cationic lipid and cholesterol, or DOPE, primarily target the lungs, where they transfect tissue-resident DCs, macrophages and endothelial cells.
“In comparison, cationic mRNA LNPs composed of a cationic lipid and cholesterol, or DOPE were found to primarily target the lungs, where they transfect tissueresident DCs, macrophages and endothelial cells [142,157,158].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [157]
Nucleoside-modified mRNA LNPs outperform unmodified mRNA LNPs in translation capacity, but fail to elicit successful CTL responses due to drastically reduced production of type I IFNs.
“Comparative studies performed by our research group and others demonstrated that nucleoside-modified mRNA LNPs outperformed unmodified mRNA LNPs in translation capacity, but failed to elicit successful CTL responses due to the drastically reduced production of type I IFNs [119,157].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [157]
In a proof-of-concept study, nucleoside-modified mRNA co-delivered with the clinically approved TLR agonist MPLA achieved functional CTL responses like unmodified mRNA, but with strongly reduced type I IFN responses.
“In a proof-of-concept study, we demonstrated that nucleoside-modified mRNA can be co-delivered with the clinically approved TLR agonist MPLA, achieving functional CTL responses like unmodified mRNA, but with strongly reduced type I IFN responses [157].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [157]
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- Authors
- Verbeke, R., Lentacker, I., Wayteck, L., Breckpot, K., Van Bockstal, M., Descamps, B., Vanhove, C., De Smedt, S. C., & Dewitte, H.
- Affiliations
- Ghent University Hospital (BE)
- Vrije Universiteit Brussel (BE)
- Ghent University (BE)
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 266
- Pages
- 287-300
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2762387202
- Cited by
- 132
- References
- 66
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 15 · 2023: 14 · 2022: 20 · 2021: 20 · 2020: 16 · 2019: 17 · 2018: 9
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- FWO (G016513N, G0B2814N)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- nucleoside-modified mRNA, TLR agonists, monophosphoryl lipid A, lipid nanoparticles, cancer immunotherapy, mRNA vaccines, type I interferon, adjuvants, antigen-presenting cells, T cell immunity
- MeSH terms
- Animals, Cytidine, Dendritic Cells, Female, Immunotherapy, Lipid A, Lipids, Mice, Inbred C57BL, Neoplasms, RNA, Messenger, Cancer Vaccines, Toll-Like Receptors
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