Skip to main content

Advertisement

Log in

mRNA-based therapeutics–Advances and perspectives

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

In this review we discuss features of mRNA synthesis and modifications used to minimize immune response and prolong efficiency of the translation process in vivo. Considerable attention is given to the use of liposomes and nanoparticles containing lipids and polymers for the mRNA delivery. Finally we briefly discuss mRNAs which are currently in the clinical trials for cancer immunotherapy, vaccination against infectious diseases, and replacement therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

CRISPR-Cas9:

system of clustered regularly interspaced short palindromic repeats and Cas9 nuclease

dsRNA:

double stranded RNA

FDA:

Food and Drug Administration (USA)

HIV:

human immunodeficiency virus

LNP:

lipid nanoparticles

mRNA:

messenger RNA

NA:

nucleic acids

ORF:

open reading frame

PEG:

polyethylene glycol

siRNA:

small interfering RNA

TALEN:

transcription activator-like effector nuclease

TLRs:

Toll-like receptors

UTR:

untranslated region

ZFN:

zinc finger nuclease

References

  1. Zamecnik, P. C., and Stephenson, M. L. (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide, Proc. Natl. Acad. Sci. USA, 75, 280–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stephenson, M. L., and Zamecnik, P. C. (1978) Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide, Proc. Natl. Acad. Sci. USA, 75, 285–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bennett, C. F., and Swayze, E. E. (2010) RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform, Annu. Rev. Pharmacol. Toxicol., 50, 259–293.

    Article  CAS  PubMed  Google Scholar 

  4. Lundin, K. E., Gissberg, O., and Smith, C. I. (2015) Oligonucleotide therapies: the past and the present, Hum. Gene Ther., 26, 475–485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dobrovolskaia, M. A., and McNeil, S. E. (2015) Immunological and hematological toxicities challenging clinical translation of nucleic acid-based therapeutics, Expert Opin. Biol. Ther., 15, 1023–1048.

    Article  CAS  PubMed  Google Scholar 

  6. Bobbin, M. L., and Rossi, J. J. (2016) RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu. Rev. Pharmacol. Toxicol., 56, 103–122.

    Article  CAS  PubMed  Google Scholar 

  7. Prakash, V., Moore, M., and Yanez-Munoz, R. J. (2016) Current progress in therapeutic gene editing for monogenic diseases, Mol. Ther., 24, 465–474.

    Article  CAS  PubMed  Google Scholar 

  8. LaFountaine, J. S., Fathe, K., and Smyth, H. D. (2015) Delivery and therapeutic applications of gene editing technologies ZFNs, TALENs, and CRISPR/Cas9, Int. J. Pharm., 494, 180–194.

    Article  CAS  PubMed  Google Scholar 

  9. Maeder, M. L., and Gersbach, C. A. (2016) Genome-editing technologies for gene and cell therapy, Mol. Ther., 24, 430–446.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lander, E. S. (2016) The heroes of CRISPR, Cell, 164, 18–28.

    Article  CAS  PubMed  Google Scholar 

  11. Lee, C. M., Cradick, T. J., Fine, E. J., and Bao, G. (2016) Nuclease target site selection for maximizing on-target activity and minimizing off-target effects in genome editing, Mol. Ther., 24, 475–487.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yin, H., Xue, W., Chen, S., Bogorad, R. L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P. A., Jacks, T., and Anderson, D. G. (2014) Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype, Nat. Biotechnol., 32, 551–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yin, H., Song, C. Q., Dorkin, J. R., Zhu, L. J., Li, Y., Wu, Q., Park, A., Yang, J., Suresh, S., Bizhanova, A., Gupta, A., Bolukbasi, M. F., Walsh, S., Bogorad, R. L., Gao, G., Weng, Z., Dong, Y., Koteliansky, V., Wolfe, S. A., Langer, R., Xue, W., and Anderson, D. G. (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo, Nat. Biotechnol., 34, 328–333.

    Article  CAS  PubMed  Google Scholar 

  14. Prazeres, D. M., and Monteiro, G. A. (2014) Plasmid biopharmaceuticals, Microbiol. Spectr., 2, doi: 10.1128/microbiolspec.PLAS-0022-2014.

  15. Meunier, M., Chemaly, M., and Dory, D. (2016) DNA vaccination of poultry: the current status in 2015, Vaccine, 34, 202–211.

    Article  CAS  PubMed  Google Scholar 

  16. Fewell, J. G., MacLaughlin, F., Mehta, V., Gondo, M., Nicol, F., Wilson, E., and Smith, L. C. (2001) Gene therapy for the treatment of hemophilia B using PINC-formulated plasmid delivered to muscle with electroporation, Mol. Ther., 3, 574–583.

    Article  CAS  PubMed  Google Scholar 

  17. Nikol, S., Baumgartner, I., Van Belle, E., Diehm, C., Visona, A., Capogrossi, M. C., Ferreira-Maldent, N., Gallino, A., Wyatt, M. G., Wijesinghe, L. D., Fusari, M., Stephan, D., Emmerich, J., Pompilio, G., Vermassen, F., Pham, E., Grek, V., Coleman, M., and Meyer, F. (2008) Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia, Mol. Ther., 16, 972–978.

    Article  CAS  PubMed  Google Scholar 

  18. Sahin, U., Kariko, K., and Ureci, O. (2014) mRNA-based therapeutics–developing a new class of drugs, Nat. Rev. Drug Discov., 13, 759–780.

    Article  CAS  PubMed  Google Scholar 

  19. Matsui, A., Uchida, S., Ishii, T., Itaka, K., and Kataoka, K. (2015) Messenger RNA-based therapeutics for the treatment of apoptosis-associated diseases, Sci. Rep., 5, 15810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., Daley, G. Q., Brack, A. S., Collins, J. J., Cowan, C., Schlaeger, T. M., and Rossi, D. J. (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA, Cell Stem Cell, 7, 618–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Uchida, S., Kataoka, K., and Itaka, K. (2015) Screening of mRNA chemical modification to maximize protein expression with reduced immunogenicity, Pharmaceutics, 7, 137–151.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mahiny, A. J., Dewerth, A., Mays, L. E., Alkhaled, M., Mothes, B., Malaeksefat, E., Loretz, B., Rottenberger, J., Brosch, D. M., Reautschnig, P., Surapolchai, P., Zeyer, F., Schams, A., Carevic, M., Bakele, M., Griese, M., Schwab, M., Nurnberg, B., Beer-Hammer, S., Handgretinger, R., Hartl, D., Lehr, C. M., and Kormann, M. S. (2015) In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency, Nat. Biotechnol., 33, 584–586.

    CAS  PubMed  Google Scholar 

  23. Mehier-Humbert, S., and Guy, R. H. (2005) Physical methods for gene transfer: improving the kinetics of gene delivery into cells, Adv. Drug Deliv. Rev., 57, 733–753.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, X., and Godbey, W. T. (2006) Viral vectors for gene delivery in tissue engineering, Adv. Drug Deliv. Rev., 58, 515–534.

    Article  CAS  PubMed  Google Scholar 

  25. Kotterman, M. A., and Schaffer, D. V. (2014) Engineering adeno-associated viruses for clinical gene therapy, Nat. Rev. Genet., 15, 445–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Andreev, D. E., Terenin, I. M., Dmitriev, S. E., and Shatsky, I. N. (2016) Pros and cons of pDNA and mRNA transfection to study mRNA translation in mammalian cells, Gene, 578, 1–6.

    Article  CAS  PubMed  Google Scholar 

  27. Gallie, D. R. (1991) The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency, Genes Dev., 5, 2108–2116.

    Article  CAS  PubMed  Google Scholar 

  28. Kuhn, A. N., Diken, M., Kreiter, S., Selmi, A., Kowalska, J., Jemielity, J., Darzynkiewicz, E., Huber, C., Tureci, O., and Sahin, U. (2010) Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immaturedendritic cells and induce superior immune responses in vivo, Gene Ther., 17, 961–971.

    Article  CAS  PubMed  Google Scholar 

  29. Stepinski, J., Waddell, C., Stolarski, R., Darzynkiewicz, E., and Rhoads, R. E. (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, 1486–1495.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Grudzien-Nogalska, E., Jemielity, J., Kowalska, J., Darzynkiewicz, E., and Rhoads, R. E. (2007) Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells, RNA, 13, 1745–1755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Loo, Y. M., Fornek, J., Crochet, N., Bajwa, G., Perwitasari, O., Martinez-Sobrido, L., Akira, S., Gill, M. A., Garcia-Sastre, A., Katze, M. G., and Gale, M. (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity, J. Virol., 82, 335–345.

    Article  CAS  PubMed  Google Scholar 

  32. Pichlmair, A., Schulz, O., Tan, C. P., Rehwinkel, J., Kato, H., Takeuchi, O., Akira, S., Way, M., Schiavo, G., and Reise Sousa, C. (2009) Activation of MDA5 requires higherorder RNA structures generated during virus infection, J. Virol., 83, 10761–10769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lu, C., Xu, H., Ranjith-Kumar, C. T., Brooks, M. T., Hou, T. Y., Hu, F., Herr, A. B., Strong, R. K., Kao, C. C., and Li, P. (2010) The structural basis of 5'-triphosphate doublestranded RNA recognition by RIG-I C-terminal domain, Structure, 18, 1032–1043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoneyama, M., and Fujita, T. (2010) Recognition of viral nucleic acids in innate immunity, Rev. Med. Virol., 20, 4–22.

    Article  CAS  PubMed  Google Scholar 

  35. Sen, G. C., and Sarkar, S. N. (2007) The interferon-stimulated genes: targets of direct signaling by interferons, double-stranded RNA, and viruses, Curr. Top. Microbiol. Immunol., 316, 233–250.

    CAS  PubMed  Google Scholar 

  36. Andries, O., De Filette, M., De Smedt, S. C., Demeester, J., Van Poucke, M., Peelman, L., and Sanders, N. N. (2013) Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells, J. Control. Release, 167, 157–166.

    Article  CAS  PubMed  Google Scholar 

  37. Kanneganti, T. D., Body-Malapel, M., Amer, A., Park, J. H., Whitfield, J., Franchi, L., Taraporewala, Z. F., Miller, D., Patton, J. T., Inohara, N., and Nunez, G. (2006) Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA, J. Biol. Chem., 281, 36560–36568.

    Article  CAS  PubMed  Google Scholar 

  38. Nallagatla, S. R., Hwang, J., Toroney, R., Zheng, X., Cameron, C. E., and Bevilacqua, P. C. (2007) 5'Triphosphate-dependent activation of PKR by RNAs with short stem-loops, Science, 318, 1455–1458.

    Article  CAS  PubMed  Google Scholar 

  39. Pardi, N., Muramatsu, H., Weissman, D., and Kariko, K. (2013) In vitro transcription of long RNA containing modified nucleosides, Methods Mol. Biol., 969, 29–42.

    Article  CAS  PubMed  Google Scholar 

  40. Brawerman, G. (1981) The role of the poly(A) sequence in mammalian messenger RNA, CRC Crit. Rev. Biochem., 10, 1–38.

    Article  CAS  PubMed  Google Scholar 

  41. Koski, G. K., Kariko, K., Xu, S., Weissman, D., Cohen, P. A., and Czerniecki, B. J. (2004) Cutting edge: innate immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells, J. Immunol., 172, 3989–3993.

    Article  CAS  PubMed  Google Scholar 

  42. Caput, D., Beutler, B., Hartog, K., Thayer, R., BrownShimer, S., and Cerami, A. (1986) Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators, Proc. Natl. Acad. Sci. USA, 83, 1670–1674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Holtkamp, S. (2006) Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells, Blood, 108, 4009–4017.

    Article  CAS  PubMed  Google Scholar 

  44. Kariko, K., Kuo, A., and Barnathan, E. (1999) Overexpression of urokinase receptor in mammalian cells following administration of the in vitro transcribed encoding mRNA, Gene Ther., 6, 1092–1100.

    Article  CAS  PubMed  Google Scholar 

  45. Diebold, S. S., Massacrier, C., Akira, S., Paturel, C., Morel, Y., and Reise Sousa, C. (2006) Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides, Eur. J. Immunol., 36, 3256–3267.

    Article  CAS  PubMed  Google Scholar 

  46. Alexopoulou, L., Holt, A. C., Medzhitov, R., and Flavell, R. A. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3, Nature, 413, 732–738.

    Article  CAS  PubMed  Google Scholar 

  47. Kariko, K., Buckstein, M., Ni, H., and Weissman, D. (2005) Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA, Immunity, 23, 165–175.

    Article  CAS  PubMed  Google Scholar 

  48. Nallagatla, S. R., and Bevilacqua, P. C. (2008) Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner, RNA, 14, 1201–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kariko, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., and Weissman, D. (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability, Mol. Ther., 16, 1833–1840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, B., Luo, X., and Dong, Y. (2016) Effects of chemically modified messenger RNA on protein expression, Bioconj. Chem., 27, 849–853.

    Article  CAS  Google Scholar 

  51. Kormann, M. S., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., Griese, M., Bittmann, I., Handgretinger, R., Hartl, D., Rosenecker, J., and Rudolph, C. (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice, Nat. Biotechnol., 29, 154–157.

    Article  CAS  PubMed  Google Scholar 

  52. Wang, X., Zhao, B. S., Roundtree, I. A., Lu, Z., Han, D., Ma, H., Weng, X., Chen, K., Shi, H., and He, C. (2015) N6-methyladenosine modulates messenger RNA translation efficiency, Cell, 161, 1388–1399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kariko, K., Muramatsu, H., Ludwig, J., and Weissman, D. (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, e142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rittig, S. M., Haentschel, M., Weimer, K. J., Heine, A., Muller, M. R., Brugger, W., Horger, M. S., Maksimovic, O., Stenzl, A., Hoerr, I., Rammensee, H. G., Holderried, T. A., Kanz, L., Pascolo, S., and Brossart, P. (2011) Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients, Mol. Ther., 19, 990–999.

    Article  CAS  PubMed  Google Scholar 

  55. Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A., and Geall, A. J. (2014) Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines, Expert Opin. Drug Deliv., 11, 885–899.

    Article  CAS  PubMed  Google Scholar 

  56. Brito, L. A., Kommareddy, S., Maione, D., Uematsu, Y., Giovani, C., Berlanda Scorza, F., Otten, G. R., Yu, D., Mandl, C. W., Mason, P. W., Dormitzer, P. R., Ulmer, J. B., and Geall, A. J. (2015) Self-amplifying mRNA vaccines, Adv. Genet., 89, 179–233.

    Article  PubMed  Google Scholar 

  57. Loomis, K. H., Kirschman, J. L., Bhosle, S., Bellamkonda, R. V., and Santangelo, P. J. (2016) Strategies for modulating innate immune activation and protein production of in vitro transcribed mRNAs, J. Mat. Chem. B, 4, 1619–1632.

    Article  CAS  Google Scholar 

  58. Islam, M. A., Reesor, E. K. G., Xu, Y., Zope, H. R., Zetter, B. R., and Shia, J. (2015) Biomaterials for mRNA delivery, Biomater. Sci., 3, 1519–1533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kauffman, K. J., Webber, M. J., and Anderson, D. G. (2015) Materials for non-viral intracellular delivery of messenger RNA therapeutics, J. Control. Release, 3 pii: S0168-3659(15)30283-2.

  60. Van Lint, S., Goyvaerts, C., Maenhout, S., Goethals, L., Disy, A., Benteyn, D., Pen, J., Bonehill, A., Heirman, C., Breckpot, K., and Thielemans, K. (2012) Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy, Cancer Res., 72, 1661–1671.

    Article  PubMed  CAS  Google Scholar 

  61. Amos, H. (1961) Protamine enhancement of RNA uptake by cultured chick cells, Biochem. Biophys. Res. Commun., 5, 1–4.

    Article  CAS  Google Scholar 

  62. Choi, Y. S., Lee, J. Y., Suh, J. S., Kwon, Y. M., Lee, S. J., Chung, J. K., Lee, D. S., Yang, V. C., Chung, C. P., and Park, Y. J. (2010) The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine, Biomaterials, 31, 1429–1443.

    Article  CAS  PubMed  Google Scholar 

  63. Kallen, K. J., Heidenreich, R., Schnee, M., Petsch, B., Schlake, T., Thess, A., Baumhof, P., Scheel, B., Koch, S. D., and Fotin-Mleczek, M. (2013) A novel, disruptive vaccination technology: self-adjuvanted RNActive® vaccines, Hum. Vaccin. Immunother., 9, 2263–2276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brito, L. A., Chan, M., Shaw, C. A., Hekele, A., Carsillo, T., Schaefer, M., Archer, J., Seubert, A., Otten, G. R., Beard, C. W., Dey, A. K., Lilja, A., Valiante, N. M., Mason, P. W., Mandl, C. W., Barnett, S. W., Dormitzer, P. R., Ulmer, J. B., Singh, M., O’Hagan, D. T., and Geall, A. J. (2014) A cationic nanoemulsion for the delivery of nextgeneration RNA vaccines, Mol. Ther., 22, 2118–2129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Safinya, C. R. (2001) Structures of lipid–DNA complexes: supramolecular assembly and gene delivery, Curr. Opin. Struct. Biol., 11, 440–448.

    Article  CAS  PubMed  Google Scholar 

  66. Mockey, M., Bourseau, E., Chandrashekhar, V., Chaudhuri, A., Lafosse, S., Le Cam, E., Quesniaux, V. F., Ryffel, B., Pichon, C., and Midoux, P. (2007) mRNAbased cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes, Cancer Gene Ther., 14, 802–814.

    Article  CAS  PubMed  Google Scholar 

  67. Hess, P. R., Boczkowski, D., Nair, S. K., Snyder, D., and Gilboa, E. (2006) Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen, Cancer Immunol. Immunother., 55, 672–683.

    Article  CAS  PubMed  Google Scholar 

  68. Pollard, C., Rejman, J., De Haes, W., Verrier, B., Van Gulck, E., Naessens, T., De Smedt, S., Bogaert, P., Grooten, J., Vanham, G., and De Koker, S. (2013) Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines, Mol. Ther., 21, 251–259.

    Article  CAS  PubMed  Google Scholar 

  69. Geall, A. J., Verma, A., Otten, G. R., Shaw, C. A., Hekele, A., Banerjee, K., Cu, Y., Beard, C. W., Brito, L. A., Krucker, T., O’Hagan, D. T., Singh, M., Mason, P. W., Valiante, N. M., Dormitzer, P. R., Barnett, S. W., Rappuoli, R., Ulmer, J. B., and Mandl, C. W. (2012) Nonviral delivery of self-amplifying RNA vaccines, Proc. Natl. Acad. Sci. USA, 109, 14604–14609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cheng, X., and Lee, R. J. (2016) The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery, Adv. Drug Deliv. Rev., 99, 129–137.

    Article  CAS  PubMed  Google Scholar 

  71. Tanaka, H., Sato, Y., Harashima, H., and Akita, H. (2016) Cellular environment-responsive nanomaterials for use in gene and siRNA delivery: molecular design for biomembrane destabilization and intracellular collapse, Expert Opin. Drug Deliv., 21, 1–13.

    Google Scholar 

  72. Maier, M. A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y. K., Ansell, S. M., Kumar, V., Qin, J., Zhang, X., Wang, Q., Panesar, S., Hutabarat, R., Carioto, M., Hettinger, J., Kandasamy, P., Butler, D., Rajeev, K. G., Pang, B., Charisse, K., Fitzgerald, K., Mui, B. L., Du, X., Cullis, P., Madden, T. D., Hope, M. J., Manoharan, M., and Akinc, A. (2013) Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics, Mol. Ther., 21, 1570–1578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., and Weissman, D. (2015) Expression kinetics of nucleosidemodified mRNA delivered in lipid nanoparticles to mice by various routes, J. Control. Release, 217, 345–351.

    Article  CAS  PubMed  Google Scholar 

  74. Naseri, N., Valizadeh, H., and Zakeri-Milani, P. (2015) Solid lipid nanoparticles and nanostructured lipid carriers: structure, preparation and application, Adv. Pharm. Bull., 5, 305–313.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Midoux, P., and Pichon, C. (2015) Lipid-based mRNA vaccine delivery systems, Expert Rev. Vaccines, 14, 221–234.

    Article  CAS  PubMed  Google Scholar 

  76. Warashina, S., Nakamura, T., Sato, Y., Fujiwara, Y., Hyodo, M., Hatakeyama, H., and Harashima, H. (2016) A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells, J. Control. Release, 225, 183–191.

    Article  CAS  PubMed  Google Scholar 

  77. Wang, Y., Rajala, A., and Rajala, R. V. (2015) Lipid nanoparticles for ocular gene delivery, J. Funct. Biomater., 6, 379–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kim, Y. D., Park, T. E., Singh, B., Maharjan, S., Choi, Y. J., Choung, P. H., Arote, R. B., and Cho, C. S. (2015) Nanoparticle-mediated delivery of siRNA for effective lung cancer therapy, Nanomedicine, 10, 1165–1188.

    Article  CAS  PubMed  Google Scholar 

  79. Li, B., Luo, X., Deng, B., Wang, J., McComb, D. W., Shi, Y., Gaensler, K. M., Tan, X., Dunn, A. L., Kerlin, B. A., and Dong, Y. (2015) An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo, Nano Lett., 15, 8099–8107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li, B., Luo, X., Deng, B., Giancola, J. B., McComb, D. W., Schmittgen, T. D., and Dong, Y. (2016) Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA, Sci. Rep., 6, 22137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., Fenton, O. S., and Anderson, D. G. (2015) Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs, Nano Lett., 15, 7300–7306.

    Article  CAS  PubMed  Google Scholar 

  82. Fenton, O. S., Kauffman, K. J., McClellan, R. L., Appel, E. A., Dorkin, J. R., Tibbitt, M. W., Heartlein, M. W., DeRosa, F., Langer, R., and Anderson, D. G. (2016) Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery, Adv. Mater., 28, 2939–2943.

    Article  CAS  PubMed  Google Scholar 

  83. Akinc, A., Querbes, W., De, S., Qin, J., FrankKamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., Butler, J. S., Qin, L., Racie, T., Sprague, A., Fava, E., Zeigerer, A., Hope, M. J., Zerial, M., Sah, D. W., Fitzgerald, K., Tracy, M. A., Manoharan, M., Koteliansky, V., Fougerolles, A., and Maier, M. A. (2010) Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms, Mol. Ther., 18, 1357–1364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kumar, V., Qin, J., Jiang, Y., Duncan, R. G., Brigham, B., Fishman, S., Nair, J. K., Akinc, A., Barros, S. A., and Kasperkovitz, P. V. (2014) Shielding of lipid nanoparticles for siRNA delivery: impact on physicochemical properties, cytokine induction, and efficacy, Mol. Ther. Nucleic Acids, 3, e210.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Markov, O. V., Mironova, N. L., Shmendel, E. V., Serikov, R. N., Morozova, N. G., Maslov, M. A., Vlassov, V. V., and Zenkova, M. A. (2015) Multicomponent mannose-containing liposomes efficiently deliver RNA in murine immature dendritic cells and provide productive anti-tumour response in murine melanoma model, J. Control. Release, 213, 45–56.

    Article  CAS  PubMed  Google Scholar 

  86. Crowley, S. T., Poliskey, J. A., Baumhover, N. J., and Rice, K. G. (2015) Efficient expression of stabilized mRNA PEG-peptide polyplexes in liver, Gene Ther., 22, 993–999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lachelt, U., and Wagner, E. (2015) Nucleic acid therapeutics using polyplexes: a journey of 50 years (and beyond), Chem. Rev., 115, 11043–11078.

    Article  PubMed  CAS  Google Scholar 

  88. Rozenkrants, A. A., and Sobolev, A. S. (2015) Polyethylenimine polyplex nanoparticles and their behavior in cells and body tissues, Izv. Akad. Nauk Ser. Khim., 2749-2755.

  89. Rejman, J., Tavernier, G., Bavarsad, N., Demeester, J., and De Smedt, S. C. (2010) mRNA transfection of cervical carcinoma and mesenchymal stem cells mediated by cationic carriers, J. Control. Release, 147, 385–391.

    Article  CAS  PubMed  Google Scholar 

  90. Demoulins, T., Milona, P., Englezou, P. C., Ebensen, T., Schulze, K., Suter, R., Pichon, C., Midoux, P., Guzman, C. A., Ruggli, N., and McCullough, K. C. (2015) Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines, Nanomedicine, 12, 711–722.

    PubMed  Google Scholar 

  91. Bettinger, T., Carlisle, R. C., Read, M. L., Ogris, M., and Seymour, L. W. (2001) Peptide-mediated RNA delivery: a novel approach for enhanced transfection of primary and post-mitotic cells, Nucleic Acids Res., 29, 3882–3891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Su, X., Fricke, J., Kavanagh, D. G., and Irvine, D. J. (2011) In vitro and in vivo mRNA delivery using lipidenveloped pH-responsive polymer nanoparticles, Mol. Pharm., 8, 774–787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mockey, M., Bourseau, E., Chandrashekhar, V., Chaudhuri, A., Lafosse, S., Le Cam, E., Quesniaux, V. F., Ryffel, B., Pichon, C., and Midoux, P. (2007) mRNAbased cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes, Cancer Gene Ther., 14, 802–814.

    Article  CAS  PubMed  Google Scholar 

  94. Uchida, H., Itaka, K., Nomoto, T., Ishii, T., Suma, T., Ikegami, M., Miyata, K., Oba, M., Nishiyama, N., and Kataoka, K. (2014) Modulated protonation of side chain aminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection, J. Am. Chem. Soc., 136, 12396–12405.

    Article  CAS  PubMed  Google Scholar 

  95. Uchida, H., Itaka, K., Uchida, S., Ishii, T., Suma, T., Miyata, K., Oba, M., Nishiyama, N., and Kataoka, K. (2016) Synthetic polyamines to regulate mRNA translation through the preservative binding of eukaryotic initiation factor 4E to the cap structure, J. Am. Chem. Soc., 138, 1478–1481.

    Article  CAS  PubMed  Google Scholar 

  96. Phua, K. K., Leong, K. W., and Nair, S. K. (2013) Transfection efficiency and transgene expression kinetics of mRNA delivered in naked and nanoparticle format, J. Control. Release, 166, 227–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Uchida, S., Kinoh, H., Ishii, T., Matsui, A., Tockary, T. A., Takeda, K. M., Uchida, H., Osada, K., Itaka, K., and Kataoka, K. (2016) Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety, Biomaterials, 82, 221–228.

    Article  CAS  PubMed  Google Scholar 

  98. Perche, F., Benvegnu, T., Berchel, M., Lebegue, L., Pichon, C., Jaffres, P. A., and Midoux, P. (2011) Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA, Nanomedicine, 7, 445–453.

    CAS  PubMed  Google Scholar 

  99. Perche, F., Gosset, D., Mevel, M., Miramon, M. L., Yaouanc, J. J., Pichon, C., Benvegnu, T., Jaffres, P. A., and Midoux, P. (2011) Selective gene delivery in dendritic cells with mannosylated and histidylated lipopolyplexes, J. Drug Target., 19, 315–325.

    Article  CAS  PubMed  Google Scholar 

  100. Srinivas, R., Karmali, P. P., Pramanik, D., Garu, A., Mahidhar, Y. V., Majeti, B. K., Ramakrishna, S., Srinivas, G., and Chaudhuri, A. (2010) Cationic amphiphile with shikimic acid headgroup shows more systemic promise than its mannosyl analogue as DNA vaccine carrier in dendritic cell based genetic immunization, J. Med. Chem., 53, 1387–1391.

    Article  CAS  PubMed  Google Scholar 

  101. Srinivas, R., Garu, A., Moku, G., Agawane, S. B., and Chaudhuri, A. (2012) A long-lasting dendritic cell DNA vaccination system using lysinylated amphiphiles with mannose-mimicking head-groups, Biomaterials, 33, 6220–6229.

    Article  CAS  PubMed  Google Scholar 

  102. Johler, S. M., Rejman, J., Guan, S., and Rosenecker, J. (2015) Nebulisation of IVT mRNA complexes for intrapulmonary administration, PLoS One, 10, e0137504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Uchida, S., Itaka, K., Uchida, H., Hayakawa, K., Ogata, T., Ishii, T., Fukushima, S., Osada, K., and Kataoka, K. (2013) In vivo messenger RNA introduction into the central nervous system using polyplex nanomicelle, PLoS One, 8, e56220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Baba, M., Itaka, K., Kondo, K., Yamasoba, T., and Kataoka, K. (2015) Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles, J. Control. Release, 201, 41–48.

    Article  CAS  PubMed  Google Scholar 

  105. Weiss, R., Scheiblhofer, S., Roesler, E., Weinberger, E., and Thalhamer, J. (2012) mRNA vaccination as a safe approach for specific protection from type I allergy, Expert Rev. Vaccines, 11, 55–67.

    Article  CAS  PubMed  Google Scholar 

  106. Scheel, B., Teufel, R., Probst, J., Carralot, J. P., Geginat, J., Radsak, M., Jarrossay, D., Wagner, H., Jung, G., Rammensee, H. G., Hoerr, I., and Pascolo, S. (2005) Tolllike receptor-dependent activation of several human blood cell types by protamine-condensed mRNA, Eur. J. Immunol., 35, 1557–1566.

    Article  CAS  PubMed  Google Scholar 

  107. Heiser, A., Coleman, D., Dannull, J., Yancey, D., Maurice, M. A., Lallas, C. D., Dahm, P., Niedzwiecki, D., Gilboa, E., and Vieweg, J. (2002) Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors, J. Clin. Invest., 109, 409–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kubler, H., Scheel, B., Gnad-Vogt, U., Miller, K., Schultze-Seemann, W., Vom Dorp, F., Parmiani, G., Hampel, C., Wedel, S., Trojan, L., Jocham, D., Maurer, T., Rippin, G., Fotin-Mleczek, M., Von der Mulbe, F., Probst, J., Hoerr, I., Kallen, K. J., Lander, T., and Stenzl, A. (2015) Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study, J. Immunother. Cancer, 3, 26.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Su, Z., Dannull, J., Heiser, A., Yancey, D., Pruitt, S., Madden, J., Coleman, D., Niedzwiecki, D., Gilboa, E., and Vieweg, J. (2003) Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells, Cancer Res., 63, 2127–2133.

    CAS  PubMed  Google Scholar 

  110. Dannull, J., Su, Z., Rizzieri, D., Yang, B. K., Coleman, D., Yancey, D., Zhang, A., Dahm, P., Chao, N., Gilboa, E., and Vieweg, J. (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T-cells, J. Clin. Invest., 115, 3623–3633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mu, L. J., Kyte, J. A., Kvalheim, G., Aamdal, S., Dueland, S., Hauser, M., Hammerstad, H., Waehre, H., Raabe, N., and Gaudernack, G. (2005) Immunotherapy with allotumour mRNA-transfected dendritic cells in androgenresistant prostate cancer patients, Br. J. Cancer, 93, 749–756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kyte, J. A., Mu, L., Aamdal, S., Kvalheim, G., Dueland, S., Hauser, M., Gullestad, H. P., Ryder, T., Lislerud, K., Hammerstad, H., and Gaudernack, G. (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA, Cancer Gene Ther., 13, 905–918.

    Article  CAS  PubMed  Google Scholar 

  113. Weide, B., Carralot, J. P., Reese, A., Scheel, B., Eigentler, T. K., Hoerr, I., Rammensee, H. G., Garbe, C., and Pascolo, S. (2008) Results of the first phase I/II clinical vaccination trial with direct injection of mRNA, J. Immunother., 31, 180–188.

    Article  CAS  PubMed  Google Scholar 

  114. Fotin-Mleczek, M., Duchardt, K. M., Lorenz, C., Pfeiffer, R., Ojkic-Zrna, S., Probst, J., and Kallen, K. J. (2011) Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity, J. Immunother., 34, 1–15.

    Article  CAS  PubMed  Google Scholar 

  115. Pascolo, S. (2008) Vaccination with messenger RNA (mRNA), Handb. Exp. Pharmacol., 183, 221–235.

    Article  CAS  PubMed  Google Scholar 

  116. Martinon, F., Krishnan, S., Lenzen, G., Magne, R., Gomard, E., Guillet, J. G., Levy, J. P., and Meulien, P. (1993) Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA, Eur. J. Immunol., 23, 1719–1722.

    Article  CAS  PubMed  Google Scholar 

  117. Petsch, B., Schnee, M., Vogel, A. B., Lange, E., Hoffmann, B., Voss, D., Schlake, T., Thess, A., Kallen, K. J., Stitz, L., and Kramps, T. (2012) Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection, Nat. Biotechnol., 30, 1210–1216.

    Article  CAS  PubMed  Google Scholar 

  118. Brazzoli, M., Magini, D., Bonci, A., Buccato, S., Giovani, C., Kratzer, R., Zurli, V., Mangiavacchi, S., Casini, D., Brito, L. M., De Gregorio, E., Mason, P. W., Ulmer, J. B., Geall, A. J., and Bertholet, S. (2015) Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin, J. Virol., 90, 332–344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Allard, S. D., De Keersmaecker, B., De Goede, A. L., Verschuren, E. J., Koetsveld, J., Reedijk, M. L., Wylock, C., De Bel, A. V., Vandeloo, J., Pistoor, F., Heirman, C., Beyer, W. E., Eilers, P. H., Corthals, J., Padmos, I., Thielemans, K., Osterhaus, A. D., Lacor, P., Van der Ende, M. E., Aerts, J. L., Van Baalen, C. A., and Gruters, R. A. (2012) A phase I/IIa immunotherapy trial of HIV-1infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption, Clin. Immunol., 142, 252–268.

    Article  CAS  PubMed  Google Scholar 

  120. Van Gulck, E., Vlieghe, E., Vekemans, M., Van Tendeloo, V. F., Van De Velde, A., Smits, E., Anguille, S., Cools, N., Goossens, H., Mertens, L., De Haes, W., Wong, J., Florence, E., Vanham, G., and Berneman, Z. N. (2012) mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients, AIDS, 26, 1–12.

    Article  CAS  Google Scholar 

  121. Mays, L. E., Ammon-Treiber, S., Mothes, B., Alkhaled, M., Rottenberger, J., Muller-Hermelink, E. S., Grimm, M., Mezger, M., Beer-Hammer, S., Von Stebut, E., Rieber, N., Nurnberg, B., Schwab, M., Handgretinger, R., Idzko, M., Hartl, D., and Kormann, M. S. (2013) Modified Foxp3 mRNA protects against asthma through an IL-10dependent mechanism, J. Clin. Invest., 123, 1216–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lui, K. O., Zangi, L., and Chien, K. R. (2014) Cardiovascular regenerative therapeutics via synthetic paracrine factor modified mRNA, Stem Cell Res., 13, 693–704.

    Article  CAS  PubMed  Google Scholar 

  123. Zangi, L., Lui, K. O., Von Gise, A., Ma, Q., Ebina, W., Ptaszek, L. M., Spater, D., Xu, H., Tabebordbar, M., Gorbatov, R., Sena, B., Nahrendorf, M., Briscoe, D. M., Li, R. A., Wagers, A. J., Rossi, D. J., Pu, W. T., and Chien, K. R. (2013) Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardialinfarction, Nat. Biotechnol., 31, 898–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell, 131, 861–872.

    Article  CAS  PubMed  Google Scholar 

  125. Yakubov, E., Rechavi, G., Rozenblatt, S., and Givol, D. (2010) Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors, Biochem. Biophys. Res. Commun., 394, 189–193.

    Article  CAS  PubMed  Google Scholar 

  126. Lee, J., Sayed, N., Hunter, A., Au, K. F., Wong, W. H., Mocarski, E. S., Pera, R. R., Yakubov, E., and Cooke, J. P. (2012) Activation of innate immunity is required for efficient nuclear reprogramming, Cell, 151, 547–558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Doyon, Y., McCammon, J. M., Miller, J. C., Faraji, F., Ngo, C., Katibah, G. E., Amora, R., Hocking T. D., Zhang, L., Rebar, E. J., Gregory, P. D., Urnov, F. D., and Amacher, S. L. (2008) Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases, Nat. Biotechnol., 26, 702–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Tesson, L., Usal, C., Menoret, S., Leung, E., Niles, B. J., Remy, S., Santiago, Y., Vincent, A. I., Meng, X., Zhang, L., Gregory, P. D., Anegon, I., and Cost, G. J. (2011) Knockout rats generated by embryo microinjection of TALENs, Nat. Biotechnol., 29, 695–696.

    Article  CAS  PubMed  Google Scholar 

  129. Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., and Jaenisch, R. (2013) Onestep generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering, Cell, 153, 910–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wilber, A., Frandsen, J. L., Geurts, J. L., Largaespada, D. A., Hackett, P. B., and McIvor, R. S. (2006) RNA as a source of transposase for sleeping beauty-mediated gene insertion and expression in somatic cells and tissues, Mol. Ther., 13, 625–630.

    Article  CAS  PubMed  Google Scholar 

  131. Furushima, K., Jang, C. W., Chen, D. W., Xiao, N., Overbeek, P. A., and Behringer, R. R. (2012) Insertional mutagenesis by a hybrid piggyBac and sleeping beauty transposon in the rat, Genetics, 192, 1235–1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bire, S., Gosset, D., Jegot, G., Midoux, P., Pichon, C., and Rouleux-Bonnin, F. (2013) Exogenous mRNA delivery and bioavailability in gene transfer mediated by piggyBac transposition, BMC Biotechnol., 13, 75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., Daley, G. Q., Brack, A. S., Collins, J. J., Cowan, C., Schlaeger, T. M., and Rossi, D. J. (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA, Cell Stem Cell, 7, 618–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to O. V. Sergeeva.

Additional information

Original Russian Text © O. V. Sergeeva, V. E. Koteliansky, T. S. Zatsepin, 2016, published in Biokhimiya, 2016, Vol. 81, No. 7, pp. 937-952.

To whom correspondence should be addressed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sergeeva, O.V., Koteliansky, V.E. & Zatsepin, T.S. mRNA-based therapeutics–Advances and perspectives. Biochemistry Moscow 81, 709–722 (2016). https://doi.org/10.1134/S0006297916070075

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916070075

Keywords

Navigation