Advances in the Study of mRNA Vaccines and Their Application in Tumor Therapy

© 2025 by the Authors. Licensee: Bio-Byword Scientific Publishing Pty Ltd, Australia. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

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Abstract

The active ingredients of traditional vaccines are pathogen antigens, mainly proteins, extracted from cells, and their production relies on large-scale cell culture, which greatly limits the speed of vaccine production and makes it difficult for humans to face large-scale epidemics such as COVID-19. In contrast, mRNA vaccine production technology is a vaccine production technology independent of cell culture. In the 1980s mRNA in vitro transcription methods were invented, in which the mRNA could encode the most effective proteins, which greatly increased the production rate. However, the body’s immune system can recognize foreign mRNA, which can trigger an inflammatory response and greatly reduce the amount of mRNA in the body and the efficiency of translation. The nucleotide in mRNA is modified by adding a Cap at 5’ end ^[1], adding Poly(A) tail at 3’ end, optimization of UTR, optimization of ORF codon, nucleoside, etc., can play a role in protecting the mRNA from being broken down by enzymes, and greatly reduce immune response triggered by mRNA. At present, there are three mRNA tumor vaccines entering the clinical application stage, namely: naked mRNA cancer vaccine, formulation mRNA cancer vaccine and dendritic cell vaccine. In the future, mRNA vaccines are expected to become effective drugs for tumor therapy. This paper reviews the working principle, mechanism and research progress of mRNA vaccines, the base modification of mRNA vaccines, and the application of mRNA vaccines in tumor therapy, with a view to providing theoretical references for the subsequent research on mRNA vaccines.

References

Granot Y, Peer D, 2017, Delivering the Right Message: Challenges and Opportunities in Lipid Nanoparticles-Mediated Modified mRNA Therapeutics—An Innate Immune System Standpoint. Semin Immunol, 34: 68–77.

Muthukrishnan S, Both G, Furuichi Y, et al., 1975, 5’-Terminal 7-Methylguanosine in Eukaryotic mRNA Is Required for Translation. Nature, 255(5503): 33–37.

Zhai T, Liu M, Lei H, 2023, Nucleoside Base Modification Inhibits RNA Immunogenicity and Enables the Development of Novel Coronavirus mRNA Vaccines. Acta Physiologica Sinica 23(10): 1–6.

Karikó K, Muramatsu H, Ludwig J, et al., 2011, Generating the Optimal mRNA for Therapy: HPLC Purification Eliminates Immune Activation and Improves Translation of Nucleoside-Modified, Protein-Encoding mRNA. Nucleic Acids Res, 39(21): e142.

Mitchell M, Billingsley M, Haley R, et al., 2021, Engineering Precision Nanoparticles for Drug Delivery. Nat Rev Drug Discov, 20(2): 101–124.

Patel A, Kaczmarek J, Bose S, et al., 2019, Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium. Adv Mater, 31(8): e1805116.

Sharp P, 2009, The Centrality of RNA. Cell, 136(4): 577–580.

Karikó K, Muramatsu H, Welsh F, et al., 2008, Incorporation of Pseudouridine into mRNA Yields Superior Nonimmunogenic Vector with Increased Translational Capacity and Biological Stability. Mol Ther, 16: 1833–1840.

Thess A, Grund S, Mui B, et al., 2015, Sequence-Engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals. Mol Ther, 23: 1456–1464.

Yu D, Ma Y, Wan F, et al., 2023, Research and Application Progress of mRNA Vaccines. Progress in Biotechnology, 13(4): 492–498.

Wolff J, Malone R, Williams P, et al., 1990, Direct Gene Transfer into Mouse Muscle in Vivo. Science, 247(4949): 1465–1468.

Conry R, Lobuglio A, Wright M, et al., 1995, Characterization of a Messenger RNA Polynucleotide Vaccine Vector. Gland Surg, 55(7): 1397–1400.

Jirikowski G, Sanna P, Maciejewski-Lenoir D, et al., 1992, Reversal of Diabetes Insipidus in Brattleboro Rats: Intrahypothalamic Injection of Vasopressin mRNA. Science, 255(5047): 996–998.

Heiser A, Coleman D, Dannull J, et al., 2002, Autologous Dendritic Cells Transfected with Prostate-Specific Antigen RNA Stimulate CTL Responses Against Metastatic Prostate Tumors. J Clin Investig, 109(3): 409–417.

Karikó K, Buckstein M, Ni H, et al., 2005, Suppression of RNA Recognition by Toll-Like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity, 23(2): 165–175.

Weide B, Pascolo S, Scheel B, et al., 2009, Direct Injection of Protamine-Protected mRNA: Results of a Phase 1/2 Vaccination Trial in Metastatic Melanoma Patients. Journal of Immunotherapy, 32(5): 498–507.

Sahin U, Kariko K, Tureci O, 2014, mRNA-Based Therapeutics—Developing a New Class of Drugs. Nat Rev Drug Discov, 13(10): 759–780.

Furuichi Y, 2015, Discovery of m(7)G-Cap in Eukaryotic mRNAs. Proc Jpn Acad Ser B Phys Biol Sci, 91(8): 394–409.

Shatkin A, 1976, Capping of Eucaryotic mRNAs. Cell, 9(4 pt 2): 645–653.

Li Y, Zhu J, Chen J, et al., 2023, Modification Strategies of mRNA Vaccines and Their Applications. Heilongjiang Journal of Animal Science and Veterinary Medicine, (13): 36–43.

Dong W, Zhang X, Chen Y, 2023, Development History and Challenges of Nucleic Acid Modification and Delivery Systems for mRNA Vaccines. Chinese Journal of Pharmaceuticals, 54(3): 304–311.

Stepinski J, Waddell C, Stolarski R, et al., 2001, Synthesis and Properties of mRNAs Containing the Novel “Anti-Reverse” Cap Analogs 7-Methyl (3’-O-Methyl) GpppG and 7-Methyl (3’-Deoxy) GpppG. RNA, 7(10): 1486–1495.

Peng Z, Sharma V, Singleton S, et al., 2002, Synthesis and Application of a Chain-Terminating Dinucleotide mRNA Cap Analog. Organic Letters, 4(2): 161–164.

Proudfoot N, 2011, Ending the Message: Poly(A) Signals Then and Now. Genes & Development, 25(17): 1770–1782.

Tian B, Graber J, 2012, Signals for Pre-mRNA Cleavage and Polyadenylation. Wiley Interdisciplinary Reviews RNA, 3(3): 385–396.

Meyer S, Urbanke C, Wahle E, 2002, Equilibrium Studies on the Association of the Nuclear Poly(A) Binding Protein with Poly(A) of Different Lengths. Biochemistry, 41(19): 6082–6089.

Brawerman G, 1981, The Role of the Poly(A) Sequence in Mammalian Messenger RNA. CRC Critical Reviews in Biochemistry, 10(1): 1–38.

Sheiness D, Darnell J, 1973, Polyadenylic Acid Segment in mRNA Becomes Shorter with Age. Nature New Biology, 241(113): 265–268.

Lawrence J, Singer R, 1986, Intracellular Localization of Messenger RNAs for Cytoskeletal Proteins. Cell, 45(3): 407–415.

Melton D, 1987, Translocation of a Localized Maternal mRNA to the Vegetal Pole of Xenopus Oocytes. Nature, 328(6125): 80–82.

Beck J, Reidenbach D, Salomon N, et al., 2021, mRNA Therapeutics in Cancer Immunotherapy. Molecular Cancer, 20: 69.

Boczkowski D, Nair S, Snyder D, et al., 1996, Dendritic Cells Pulsed with RNA Are Potent Antigen-Presenting Cells in Vitro and in Vivo. Journal of Experimental Medicine, 184: 465–472.

Miao L, Zhang Y, Huang L, 2021, mRNA Vaccine for Cancer Immunotherapy. Molecular Cancer, 20: 41.

Sahin U, Derhovanessian E, Miller M, et al., 2017, Personalized RNA Mutanome Vaccines Mobilize Poly-Specific Therapeutic Immunity Against Cancer. Nature, 547: 222–226.

Rittig S, Haentschel M, Weimer K, et al., 2011, Intradermal Vaccinations with RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients. Molecular Therapy, 19: 990–999.

Hollingsworth R, Jansen K, 2019, Turning the Corner on Therapeutic Cancer Vaccines. NPJ Vaccines, 4: 7.

Hou X, Zaks T, Langer R, et al., 2021, Lipid Nanoparticles for mRNA Delivery. Nature Reviews Materials, 6: 1078–1094.

Hong S, Zhang Z, Liu H, et al., 2018, B Cells Are the Dominant Antigen-Presenting Cells That Activate Naive CD4+ T Cells Upon Immunization with a Virus-Derived Nanoparticle Antigen. Immunity, 49: 695–708.e4.

Guan S, Rosenecker J, 2017, Nanotechnologies in Delivery of mRNA Therapeutics Using Nonviral Vector-Based Delivery Systems. Gene Therapy, 24: 133–143.

Midoux P, Pichon C, 2015, Lipid-Based mRNA Vaccine Delivery Systems. Expert Review of Vaccines, 14: 221–234.

Sebastian M, Schröder A, Scheel B, et al., 2019, A Phase I/IIa Study of the mRNA-Based Cancer Immunotherapy CV9201 in Patients with Stage IIIB/IV Non-Small Cell Lung Cancer. Cancer Immunology, Immunotherapy, 68: 799–812.

Papachristofilou A, Hipp M, Klinkhardt U, et al., 2019, Phase Ib Evaluation of a Self-Adjuvanted Protamine Formulated mRNA-Based Active Cancer Immunotherapy, BI1361849 (CV9202), Combined with Local Radiation Treatment in Patients with Stage IV Non-Small Cell Lung Cancer. Journal of Immunotherapy of Cancer, 7: 38.

Pardi N, Hogan M, Porter F, et al., 2018, mRNA Vaccines—A New Era in Vaccinology. Nature Reviews Drug Discovery, 17: 261–279.

Wykes M, Pombo A, Jenkins C, et al., 1998, Dendritic Cells Interact Directly with Naive B Lymphocytes to Transfer Antigen and Initiate Class Switching in a Primary T-Dependent Response. Journal of Immunology (Baltimore, Md.: 1950), 161(3): 1313–1319.

De Keersmaecker B, Claerhout S, Carrasco J, et al., 2020, TriMix and Tumor Antigen mRNA Electroporated Dendritic Cell Vaccination Plus Ipilimumab: Link Between T-Cell Activation and Clinical Responses in Advanced Melanoma. Journal of Immunotherapy of Cancer, 8: e000329.

Anguille S, Velde A, Smits E, et al., 2017, Dendritic Cell Vaccination as Postremission Treatment to Prevent or Delay Relapse in Acute Myeloid Leukemia. Blood, 130: 1713–1721.

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