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mRNA-based therapeutics--developing a new class of drugs
Open accessAbstract
In vitro transcribed (IVT) mRNA has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Advances in addressing the inherent challenges of this drug class, particularly related to controlling the translational efficacy and immunogenicity of the IVTmRNA, provide the basis for a broad range of potential applications. mRNA-based cancer immunotherapies and infectious disease vaccines have entered clinical development. Meanwhile, emerging novel approaches include in vivo delivery of IVT mRNA to replace or supplement proteins, IVT mRNA-based generation of pluripotent stem cells and genome engineering using IVT mRNA-encoded designer nucleases. This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.
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In the citing paper
“mRNA vaccines still suffer from decreased efficacy due to poor RNA stability in solution and in vivo and to limited expression of the payload mRNA; these are all pivotal issues that need to be carefully optimized for preclinical and clinical applications3–6.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In particular, we focused on ψ and m1ψ, since these substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and to better control of innate immune responses2,3,8,67 through avoidance of recognition by cellular toll-like receptors (TLR7 and TLR8)68, RIG‑I, and PKR69–71.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“IVT is a low-cost method of mRNA synthesis; however the immunogenicity of mRNA is the most challenging obstacle it faces (Sahin et al. 2014).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The 3ʹ-UTRs of α- and β-globin mRNAs are found in many in vitro-transcribed (IVT) mRNA, and they contain sequence features that enhance the translation and stability of mRNA (Sahin et al. 2014; Karikó et al. 1999).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
The cited source says what the claim attributes to it.
In the citing paper
“The 7-methylguanosine (m7G) moiety is found at the 5′ end of natural mRNA in the eukaryotic cytoplasm, followed by a triphosphate connection to the first nucleotide (m7GpppN) (Sahin et al. 2014).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
The cited source says what the claim attributes to it.
In the citing paper
“The basic structure of mRNA, same as eukaryotic mRNA, is made up of (i) protein encoding ORF, surrounded by (ii) 5′ and 3′ UTRs, and (iii) a 7-methyl guanosine 5′ cap structure and (iv) a 3′poly(A) tail at the end sides (Verbeke et al. 2019; Schlake et al. 2012; Sahin et al. 2014) (Fig. 1).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
The cited source says what the claim attributes to it.
In the citing paper
“The 3ʹ-UTRs of α- and β-globin mRNAs are found in many in vitro-transcribed (IVT) mRNA, and they contain sequence features that enhance the translation and stability of mRNA (Sahin et al. 2014; Karikó et al. 1999).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
The cited source says what the claim attributes to it.
In the citing paper
“IVT is a low-cost method of mRNA synthesis; however the immunogenicity of mRNA is the most challenging obstacle it faces (Sahin et al. 2014).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Sahin et al. 2014
In the citing paper
“Since the 3′-OH group in proximity to m7G is methylated, thus the ARCA cap analog can only bind the 5′ end of mRNA in forward orientation, which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) to initiate ribosome recruitment and translation.74,125”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [74]
In the citing paper
“The host immune system can easily recognize unmodified mRNA or by-products formed during IVT of engineered mRNA as exogenous molecules.74”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [74]
In the citing paper
“Tfh cells recognize antigens on the APC surface and help to activate B cells, which in turn produce high-affinity virus-neutralizing antibodies.6,55, 56, 57”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [57]
In the citing paper
“Tfh cells further help activate CD8+ cytotoxic T cells that may specifically recognize and eliminate virus-infected cells (Figure 1).6,55, 56, 57”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [57]
In the citing paper
“mRNA has shown therapeutic potential in a range of applications, including viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing2,4,7–17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“These elements can be engineered to improve the stability and translational efficiency of mRNA2,4,7,13.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“mRNA is susceptible to degradation and, thus, formulation buffers should be free of any ribonuclease contaminations2,4.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“mRNA normally contains five structural elements, that is, a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4,7,13.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Chromatographic purification can remove double-stranded RNA, an analogue of viral genome, in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency2,4,7,183.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Many other lipid nanoparticle–mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders2,4,8,12–14 (Tables 1,2).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation2,4,7,182.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“To address these concerns, the engineering of mRNA molecules (Box 1) and the design of lipid nanoparticles have been optimized2,4,7–17, which has contributed to the rapid development and clinical assessment15,17 of the two COVID-19 mRNA vaccines, mRNA-1273 (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Finally, GMP-grade lipid nanoparticle-mRNA vaccines can be manufactured for specific antigens in a short period of time, compared with other vaccine platforms, such as recombinant proteins and inactivated vaccines2,4,15,17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Moreover, mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies2,4,8,12–14.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Compared with regular mRNA, self-amplifying RNA (also termed replicon), which was originally derived from an alphavirus genome, has similar basic elements (5′ cap, 5′ and 3′ untranslated regions, 3′ poly(A) tail) and a long coding region.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“After delivery into the cytoplasm, self-amplifying RNA (positive-strand mRNA) functions as a translation template for the production of the RDRP.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“The coding region contains the sequences for an RNA-dependent RNA polymerase (RDRP), a promoter and structural viral proteins (also known as subgenomic sequence).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Meanwhile, the promoter in the negative-strand RNA is recognized by the RDRP, leading to the transcription of capped subgenomic RNA that encodes structural viral proteins.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“This self-amplification process allows the mass production of virions from limited amounts of virus at infection.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Replacing the subgenomic sequence by a gene of interest enables high-level expression of desired proteins.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“The initial replication leads to negative-strand RNA, which acts as template for the generation of the positive-strand viral genome.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“The transient replication generates double-stranded RNA (dsRNA) and, thus, self-amplifying RNA tends to activate innate immune pathways.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“Moreover, the positive-strand mRNA serves as a genomic template for RDRP-mediated replication.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“To achieve effective translation, mRNA requires five structural elements, including the 5′ cap, 3′ poly(A) tail, protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“The sequences of these elements regulate translation initiation, translation termination and post-transcriptional modification of mRNA molecules2,4.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [2]
In the citing paper
“mRNA functions as the bridge between DNA and proteins in eukaryotic cells.[8, 12, 119]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [119]
In the citing paper
“Compared with protein drugs, mRNA can supplement both cytoplasmic and large transmembranic proteins.[8, 119, 120]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [119]
In the citing paper
“Relative to plasmid DNA (pDNA), mRNA possesses temporary bioactivity and functions outside the nucleus, leading to a more controllable protein expression and avoiding the potential insertion of the genome.[8, 119, 120]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [119]
In the citing paper
“Protein-encoding mRNA has emerged as an attractive new technology for gene delivery.1”
From Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening (2019) · cites this paper as [1]
In the citing paper
“Robust induction of an immune response by a cancer vaccine requires efficient expression of the vaccine antigen-encoding mRNA specifically in DCs to achieve a high density of epitope-loaded MHCs.1,42”
From Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening (2019) · cites this paper as [1]
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Metadata
- Authors
- Sahin, U., Karikó, K., & Türeci, Ö.
- Affiliations
- BioNTech (Germany) (DE)
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Karikó, Katalin
- Türeci, Özlem
- Venue
- Nature Reviews Drug Discovery
- Published
- 2014-09-19
- Volume
- 13
- Issue
- 10
- Pages
- 759-780
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W1963706689
- Cited by
- 2,474
- References
- 256
- Citations by year
- 2026: 296 · 2025: 348 · 2024: 341 · 2023: 312 · 2022: 339 · 2021: 289 · 2020: 143 · 2019: 115 · 2018: 98 · 2017: 81 · 2016: 77 · 2015: 32 · 2014: 2
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- in vitro transcribed mRNA, mRNA therapeutics, mRNA vaccines, cancer immunotherapy, protein replacement therapy, genome editing, designer nucleases, immunogenicity, biopharmaceutical development
- MeSH terms
- Animals, Humans, Immunotherapy, Proteins, RNA, Messenger, Drug Design, Drug Delivery Systems, Pluripotent Stem Cells
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