mRNA-based therapeutics--developing a new class of drugs

Sahin, Ugur; Karikó, Katalin; Türeci, Özlem

doi:10.1038/nrd4278

Cited by 2,474RNA Interference and Gene DeliveryRNA and protein synthesis mechanismsImmunotherapy and Immune Responses

mRNA-based therapeutics--developing a new class of drugs

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Sahin, Ugur, Karikó, Katalin, Türeci, Özlem·2014·Nature Reviews Drug Discovery

DOI 10.1038/nrd4278

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Abstract

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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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.
“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]
The sections on improving mRNA delivery and on translation and stability describe extracellular degradation, intracellular stability, and achieving sufficient expression of the encoded protein as challenges. But Box 4 says RNA is stable in RNase-free environments, while the Conclusions say mRNA instability has been efficiently addressed. The paper therefore does not support a blanket claim that poor stability in solution and in vivo still reduces vaccine efficacy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
ψ and m1ψ substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and better control of innate immune responses.
“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]
Box 1 reports that pseudouridine-modified mRNA can improve translation and reduce innate immune activation, including activation of TLR7 and TLR8. It does not identify m1ψ or establish that both substitutions were widely adopted for mRNA therapeutics and vaccines. No page number is available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
The immunogenicity of mRNA is the most challenging obstacle it faces.
“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
The “Immune-stimulatory activity of IVT mRNA” section calls innate immune activation a major disadvantage for protein-replacement therapies, but an added benefit for vaccination. It does not identify immunogenicity as the most challenging obstacle for mRNA generally; the “Progress in improving mRNA delivery” section also describes substantial delivery challenges. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
α- and β-globin 3′ UTRs contain sequence features that enhance the translation and stability of mRNA.
“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 basic structure of mRNA is made up of a protein-encoding ORF, surrounded by 5′ and 3′ UTRs, a 7-methyl guanosine 5′ cap structure, and a 3′ poly(A) tail.
“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 3′ UTRs of α- and β-globin mRNAs are found in many in vitro-transcribed (IVT) mRNA.
“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 ARCA cap analog can only bind the 5′ end of mRNA in forward orientation, which is recognized by eIF4E to initiate ribosome recruitment and translation.
“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]
The host immune system can easily recognize unmodified mRNA or by-products formed during IVT of engineered mRNA as exogenous molecules.
“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]
Tfh cells recognize antigens on the APC surface and help to activate B cells, which in turn produce high-affinity virus-neutralizing antibodies.
“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]
Tfh cells further help activate CD8+ cytotoxic T cells that may specifically recognize and eliminate virus-infected cells.
“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]
mRNA has therapeutic potential in viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing.
“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]
These elements can be engineered to improve the stability and translational efficiency of mRNA.
“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]
mRNA is susceptible to degradation and, thus, formulation buffers should be free of any ribonuclease contaminations.
“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]
mRNA normally contains five structural elements: a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions.
“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]
Chromatographic purification can remove double-stranded RNA in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency.
“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]
Many other lipid nanoparticle-mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders.
“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]
Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation.
“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]
Engineering of mRNA molecules and design of lipid nanoparticles have been optimized, contributing to the rapid development and clinical assessment of the two COVID-19 mRNA vaccines.
“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]
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 vaccines.
“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]
mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies.
“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]
Self-amplifying RNA has similar basic elements to regular mRNA and a long coding region.
“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]
After delivery into the cytoplasm, self-amplifying RNA functions as a translation template for the production of the RNA-dependent RNA polymerase.
“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]
The coding region of self-amplifying RNA contains sequences for an RNA-dependent RNA polymerase, a promoter and structural viral proteins.
“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]
The promoter in the negative-strand RNA is recognized by the RNA-dependent RNA polymerase, leading to transcription of capped subgenomic RNA that encodes structural viral proteins.
“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]
The self-amplification process allows the mass production of virions from limited amounts of virus at infection.
“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]
Replacing the subgenomic sequence of self-amplifying RNA by a gene of interest enables high-level expression of desired proteins.
“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]
Initial replication of self-amplifying RNA leads to negative-strand RNA, which acts as a template for the generation of the positive-strand viral genome.
“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]
Transient replication of self-amplifying RNA generates double-stranded RNA and thus self-amplifying RNA tends to activate innate immune pathways.
“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]
The positive-strand self-amplifying RNA serves as a genomic template for RNA-dependent RNA polymerase-mediated replication.
“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]
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.
“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]
The sequences of these mRNA structural elements regulate translation initiation, translation termination and post-transcriptional modification of mRNA molecules.
“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]
mRNA functions as the bridge between DNA and proteins in eukaryotic cells.
“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]
Compared with protein drugs, mRNA can supplement both cytoplasmic and large transmembranic proteins.
“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]
Relative to plasmid DNA, mRNA possesses temporary bioactivity and functions outside the nucleus, leading to more controllable protein expression and avoiding potential insertion of the genome.
“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]
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).
“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
IVT is a low-cost method of mRNA synthesis.
“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

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mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667 · see citing works
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Authors: Sahin, U., Karikó, K., & Türeci, Ö.
Affiliations: BioNTech (Germany) (DE)
Johannes Gutenberg University Mainz (DE)
Corresponding author: Karikó, Katalin
Türeci, Özlem
ORCID: Karikó, Katalin
Türeci, Özlem
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2014-09-19
Volume: 13
Issue: 10
Pages: 759-780
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd4278
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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