Engineering a Novel Modular Adenoviral MRNA Delivery Platform Based on Tag/Catcher Bioconjugation

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2023 Nov 25

PMID 38005953

Authors

Kexin Geng

Paul J Rice-Boucher

Elena A Kashentseva

Igor P Dmitriev

Zhi Hong Lu

S Peter Goedegebuure

William E Gillanders

David T Curiel

Affiliations

Soon will be listed here.

Abstract

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, the mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors integrating Tag/Catcher proteins at specific locales on the Ad capsid proteins, allowing us to anchor mRNA to the surface of engineered Ad viruses. In proof-of-concept studies, the Ad-mRNA platform successfully mediated mRNA delivery and could be optimized via the highly flexible modular design of both the Ad-mRNA and protein bioconjugation systems.

References

To K, Cho W . An overview of rational design of mRNA-based therapeutics and vaccines. Expert Opin Drug Discov. 2021; 16(11):1307-1317. DOI: 10.1080/17460441.2021.1935859. View

Dicks M, Rose L, Russell R, Bowman L, Graham C, Jimenez-Guardeno J . Modular capsid decoration boosts adenovirus vaccine-induced humoral immunity against SARS-CoV-2. Mol Ther. 2022; 30(12):3639-3657. PMC: 9364715. DOI: 10.1016/j.ymthe.2022.08.002. View

Orlandini von Niessen A, Poleganov M, Rechner C, Plaschke A, Kranz L, Fesser S . Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening. Mol Ther. 2019; 27(4):824-836. PMC: 6453560. DOI: 10.1016/j.ymthe.2018.12.011. View

Ma H, Cao M . Designed Peptide Assemblies for Efficient Gene Delivery. Langmuir. 2022; 38(45):13627-13634. DOI: 10.1021/acs.langmuir.2c02197. View

Hangalapura B, Timares L, Oosterhoff D, Scheper R, Curiel D, de Gruijl T . CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J Gene Med. 2012; 14(6):416-27. PMC: 3433169. DOI: 10.1002/jgm.1648. View

Greber U, Flatt J . Adenovirus Entry: From Infection to Immunity. Annu Rev Virol. 2019; 6(1):177-197. DOI: 10.1146/annurev-virology-092818-015550. View

Linares-Fernandez S, Lacroix C, Exposito J, Verrier B . Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response. Trends Mol Med. 2019; 26(3):311-323. DOI: 10.1016/j.molmed.2019.10.002. View

Scheel B, Braedel S, Probst J, Carralot J, Wagner H, Schild H . Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol. 2004; 34(2):537-47. DOI: 10.1002/eji.200324198. View

Baden L, El Sahly H, Essink B, Kotloff K, Frey S, Novak R . Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020; 384(5):403-416. PMC: 7787219. DOI: 10.1056/NEJMoa2035389. View

10.

Anderson B, Muramatsu H, Jha B, Silverman R, Weissman D, Kariko K . Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res. 2011; 39(21):9329-38. PMC: 3241635. DOI: 10.1093/nar/gkr586. View

11.

Scheel B, Teufel R, Probst J, Carralot J, Geginat J, Radsak M . Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA. Eur J Immunol. 2005; 35(5):1557-66. DOI: 10.1002/eji.200425656. View

12.

Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C . Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood. 2006; 108(13):4009-17. DOI: 10.1182/blood-2006-04-015024. View

13.

Anderson B, Muramatsu H, Nallagatla S, Bevilacqua P, Sansing L, Weissman D . Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. 2010; 38(17):5884-92. PMC: 2943593. DOI: 10.1093/nar/gkq347. View

14.

Curiel D, Wagner E, Cotten M, Birnstiel M, Agarwal S, Li C . High-efficiency gene transfer mediated by adenovirus coupled to DNA-polylysine complexes. Hum Gene Ther. 1992; 3(2):147-54. DOI: 10.1089/hum.1992.3.2-147. View

15.

McErlean E, McCrudden C, McBride J, Cole G, Kett V, Robson T . Rational design and characterisation of an amphipathic cell penetrating peptide for non-viral gene delivery. Int J Pharm. 2021; 596:120223. DOI: 10.1016/j.ijpharm.2021.120223. View

16.

Keeble A, Turkki P, Stokes S, Khairil Anuar I, Rahikainen R, Hytonen V . Approaching infinite affinity through engineering of peptide-protein interaction. Proc Natl Acad Sci U S A. 2019; 116(52):26523-26533. PMC: 6936558. DOI: 10.1073/pnas.1909653116. View

17.

Goel R, Painter M, Apostolidis S, Mathew D, Meng W, Rosenfeld A . mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science. 2021; 374(6572):abm0829. PMC: 9284784. DOI: 10.1126/science.abm0829. View

18.

Dhama K, Dhawan M, Tiwari R, Emran T, Mitra S, Rabaan A . COVID-19 intranasal vaccines: current progress, advantages, prospects, and challenges. Hum Vaccin Immunother. 2022; 18(5):2045853. PMC: 8935456. DOI: 10.1080/21645515.2022.2045853. View

19.

Wculek S, Cueto F, Mujal A, Melero I, Krummel M, Sancho D . Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019; 20(1):7-24. DOI: 10.1038/s41577-019-0210-z. View

20.

Cao J, Novoa E, Zhang Z, Chen W, Liu D, Choi G . High-throughput 5' UTR engineering for enhanced protein production in non-viral gene therapies. Nat Commun. 2021; 12(1):4138. PMC: 8260622. DOI: 10.1038/s41467-021-24436-7. View