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Cited by 584RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvanced Drug Delivery Systems

The DOI matches its Crossref record; 181 of the 184 references it cites were found in a registry or an index.

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

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Wadhwa, Abishek, Aljabbari, Anas, Lokras, Abhijeet, Foged, Camilla, Thakur, Aneesh·2020·Pharmaceutics
DOI 10.3390/pharmaceutics12020102PMC PMC7076378
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Abstract

In the past few years, there has been increasing focus on the use of messenger RNA (mRNA) as a new therapeutic modality. Current clinical efforts encompassing mRNA-based drugs are directed toward infectious disease vaccines, cancer immunotherapies, therapeutic protein replacement therapies, and treatment of genetic diseases. However, challenges that impede the successful translation of these molecules into drugs are that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system. Although some of these challenges have been partially solved by means of chemical modification of the mRNA, intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions. Here, we (i) review opportunities and challenges in the delivery of mRNA-based therapeutics with a focus on non-viral delivery systems, (ii) present the clinical status of mRNA vaccines, and (iii) highlight perspectives on the future of this promising new type of medicine.

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Figure 1 Mechanism of action of mRNA vaccines. 1. The mRNA is in vitro transcribed (IVT) from a DNA template in a cell-free system. 2. IVT mRNA is subsequently transfected into dendritic cells (DCs) via (3) endocytosis. 4. Entrapped mRNA undergoes endosomal escape and is released into the cytosol. 5. Using the translational machinery of host cells (ribosomes), the mRNA is translated into antigenic proteins. The translated antigenic protein undergoes post-translational modification and can act in the cell where it is generated. 6. Alternatively, the protein is secreted from the host cell. 7. Antigen protein is degraded by the proteasome in the cytoplasm. The generated antigenic peptide epitopes are transported into the endoplasmic reticulum and loaded onto major histocompatibility complex (MHC) class I molecules (MHC I). 8. The loaded MHC I-peptide epitope complexes are presented on the surface of cells, eventually leading to the induction of antigen-specific CD8+ T cell responses after T-cell receptor recognition and appropriate co-stimulation. 9. Exogenous proteins are taken up DCs. 10. They are degraded in endosomes and presented via the MHC II pathway. Moreover, to obtain cognate T-cell help in antigen-presenting cells, the protein should be routed through the MHC II pathway. 11. The generated antigenic peptide epitopes are subsequently loaded onto MHC II molecules. 12. The loaded MHC II-peptide epitope complexes are presented on the surface of cells, leading to the induction of the antigen-specific CD4+ T cell responses. Exogenous antigens can also be processed and loaded onto MHC class I molecules via a mechanism known as cross-presentation (not shown in the figure). The figure was created with BioRender.com.
Figure 1 Mechanism of action of mRNA vaccines. 1. The mRNA is in vitro transcribed (IVT) from a DNA template in a cell-free system. 2. IVT mRNA is subsequently transfected into dendritic cells (DCs) via (3) endocytosis. 4. Entrapped mRNA undergoes endosomal escape and is released into the cytosol. 5. Using the translational machinery of host cells (ribosomes), the mRNA is translated into antigenic proteins. The translated antigenic protein undergoes post-translational modification and can act in the cell where it is generated. 6. Alternatively, the protein is secreted from the host cell. 7. Antigen protein is degraded by the proteasome in the cytoplasm. The generated antigenic peptide epitopes are transported into the endoplasmic reticulum and loaded onto major histocompatibility complex (MHC) class I molecules (MHC I). 8. The loaded MHC I-peptide epitope complexes are presented on the surface of cells, eventually leading to the induction of antigen-specific CD8+ T cell responses after T-cell receptor recognition and appropriate co-stimulation. 9. Exogenous proteins are taken up DCs. 10. They are degraded in endosomes and presented via the MHC II pathway. Moreover, to obtain cognate T-cell help in antigen-presenting cells, the protein should be routed through the MHC II pathway. 11. The generated antigenic peptide epitopes are subsequently loaded onto MHC II molecules. 12. The loaded MHC II-peptide epitope complexes are presented on the surface of cells, leading to the induction of the antigen-specific CD4+ T cell responses. Exogenous antigens can also be processed and loaded onto MHC class I molecules via a mechanism known as cross-presentation (not shown in the figure). The figure was created with BioRender.com.CC BY · PubMed Central
Figure 2 Structure of in vitro transcribed (IVT) mRNA and commonly used modification strategies. The design of IVT mRNA is based on the blueprint of eukaryotic mRNA, and it consists of a 5’ cap, 5’ and 3’ untranslated regions (UTRs), an open reading frame (ORF) encoding antigen(s), and a 3’ poly(A) tail. The IVT mRNA can be modified in one or multiple sites, e.g., by modification of the caps, the UTRs and/or the poly(A) tail, to modulate the duration and kinetic profile of protein expression. eIF4E, eukaryotic translation initiation factor 4E.
Figure 2 Structure of in vitro transcribed (IVT) mRNA and commonly used modification strategies. The design of IVT mRNA is based on the blueprint of eukaryotic mRNA, and it consists of a 5’ cap, 5’ and 3’ untranslated regions (UTRs), an open reading frame (ORF) encoding antigen(s), and a 3’ poly(A) tail. The IVT mRNA can be modified in one or multiple sites, e.g., by modification of the caps, the UTRs and/or the poly(A) tail, to modulate the duration and kinetic profile of protein expression. eIF4E, eukaryotic translation initiation factor 4E.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Shin, D., Azizian, K.T., Henderson, J.M., Lebedev, A., Hogrefe, R.I., Houston, M., McCaffrey, A.P., and BioTechnologies, T. (2018). Exploring the Messenger RNA Capping Code: CleanCap Co-Transcriptional Capping Allows Synthesis of Cap 0, Cap 1, Cap 2 and (M6) A (M) Capped RNAs, Cell Press.
  2. Sahin, U., Karikó, K., and Türeci, Ö. (2014). mRNA-based therapeutics — developing a new class of drugs. Nat. Pub. Gr. · DOI · Paper page

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Metadata

Authors
Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C., & Thakur, A.
Affiliations
University of Copenhagen (DK)
Corresponding author
Thakur, Aneesh
ORCID
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2020-01-28
Volume
12
Issue
2
Pages
102
ISSN
1999-4923 (ISSN-L)
DOI
10.3390/pharmaceutics12020102
PMC
PMC7076378
OpenAlex
W3004416358
Cited by
584
References
184
Citations by year
2026: 55 · 2025: 110 · 2024: 90 · 2023: 109 · 2022: 125 · 2021: 76 · 2020: 19
FWCI
7.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmaceutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Det Frie Forskningsråd (9041-00198B)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
mRNA vaccines, mRNA delivery, mRNA stability, nucleic acid degradation, immune activation, clinical translation, cancer immunotherapy, genetic disease treatment

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