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Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across
Open accessAbstract
The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.
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“However, the current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups5,19–28.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [5]
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“saRNAs use an RNA-dependent RNA polymerase from an alphavirus and the corresponding conserved sequence elements at the 5′ and 3′ ends for replication, leading to robust and durable expression of encoded protein cargo5–7.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [5]
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“The early and intense type I IFN response induced by saRNA detection hinders replication and antigen expression, similar to unmodified mRNA5,13–15.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [5]
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Metadata
- Authors
- Minnaert, A.-K., Vanluchene, H., Verbeke, R., Lentacker, I., De Smedt, S. C., Raemdonck, K., Sanders, N. N., & Remaut, K.
- Affiliations
- Ghent University (BE)
- Corresponding author
- Remaut, Katrien
- ORCID
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 176
- Pages
- 113900
- ISSN
- 0169-409X (ISSN-L)
- PMC
- PMC8325057
- OpenAlex
- W3187029494
- Cited by
- 157
- References
- 253
- Citations by year
- 2026: 32 · 2025: 42 · 2024: 30 · 2023: 25 · 2022: 23 · 2021: 5
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- European Commission (HORIZON2020, 810685)
- Fonds Wetenschappelijk Onderzoek (1S28420N, 11A6320N)
- Universiteit Gent
- Vlaamse regering (BOF20/PDO/041, 11A6320N)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA therapeutics, self-amplifying mRNA, innate immunity, mRNA vaccines, mRNA translation, immunotherapy, COVID-19 vaccines
- MeSH terms
- COVID-19, mRNA Vaccines, Animals, Gene Amplification, Humans, Immunity, Innate, Immunotherapy, RNA, Messenger, Vaccines, Synthetic
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