The efficacy of mRNA vaccines depends on their successful delivery into cells. Due to their large size and instability, mRNA molecules require specialized delivery systems to prevent degradation and promote cellular uptake. Scientists are optimizing various novel delivery platforms to harness mRNA’s therapeutic power.
Download this poster from Drug Discovery News to explore different mRNA vaccine delivery strategies and learn how they enhance mRNA’s therapeutic effects in cells.
mRNA Vaccine Delivery Platforms
By Kathryn Loydall, PhD
Illustrated by Kristyn Reid
One limitation encountered in mRNA vaccine production is the low stability of mRNA and its easy degradation by extracellular RNase. Its large size is also a problem; mRNA is three to four orders of magnitude larger than molecules that readily diffuse into cells. Furthermore, it is negatively charged and therefore repelled by anionic cell membranes (1). Consequently, the main challenge to developing mRNA vaccines lies in optimizing mRNA delivery systems. Its encapsulation is essential to fully harnessing mRNA’s therapeutic power. In addition to protecting the mRNA from degradation, encapsulation also promotes cellular uptake. Researchers are approaching this problem by using various delivery platforms (2).
Lipid-based
Lipid-based formulations are the most developed tools for mRNA delivery. Lipoplexes are synthetic, non-viral, cationic liposomes that are readily bound by negatively charged mRNA. Lipid nanoparticles (LNPs) are rings of positively charged ionizable lipids, which bind to and encapsulate mRNA. They contain pegylated lipids that help stabilize the particle and phospholipids and cholesterol molecules as structural components. Both BioNTech/Pfizer’s and Moderna’s mRNA SARS-CoV-2 vaccines use lipid nanoparticles as mRNA carriers (1).
Polymer-based
Polymeric materials such as polyamines, dendrimers, and copolymers are used to deliver mRNA, protect it from degradation, and facilitate intracellular delivery.(3) They coat and protect mRNA from degradation and promote protein expression. To improve therapeutic effects, scientists sometimes add lipids or branched molecules (2).
Peptide-based
Polypeptide formulations including protamine and cell-penetrating peptides are commonly used as mRNA-delivery systems (4,5). Researchers used protamine, a cationic peptide mixture, in many early mRNA vaccine studies because, in solution, it spontaneously forms a complex, the size of which is dependent on NaCl concentration (6).
Hybrids
Various hybrid nanomolecules exist for shuttling mRNA, including lipopolyplexes and cationic nanoemulsions. Researchers have used cationic nanoemulsions for packaging self-amplifying mRNA as a vaccine (7).
Metals
Recently, scientists have used numerous nanomaterials, such as gold NPs (AuNPs), to deliver mRNA in influenza and HIV vaccine studies (8,9). AuNPs have an inherent ability to tune and upregulate the immune response and act as adjuvants (10).
Virus-like particles
Scientists use virus-like particles (VLPs) to package and deliver self-amplifying RNA to the cytosol. VLP delivery enhanced mRNA uptake by dendritic cells (DCs), and the presence of anti-VLP antibodies enhanced mRNA levels and DCs in vitro in a recent study (11).
Dendritic cells
Researchers load dendritic cells (DCs) ex vivo with mRNA and re-infuse them into vaccine recipients to initiate an immune response. Most ex vivo-loaded DC vaccines elicit a predominantly cell-mediated immune response, and have been used primarily to treat cancer (12).
References
1. Let’s talk about lipid nanoparticles. Nat. Rev.Mater. 6, 99 (2021).
2. Wang, Y. et al. mRNA vaccine: a potential therapeutic strategy. Mol. Cancer 20, 33 (2021).
3. Zeng, C., Zhang, C., Walker, P.G., & Dong, Y. Current Topics in Microbiology and Immunology. (Springer, Berlin, Heidelberg, 2020).
4. Okay, S., Özcan, O.O., & Karahan, M. Nanoparticle-based delivery platforms for mRNA vaccine development. AIMS Biophysics 7(4), 323-338 (2020).
5. Jarzebska, N.T., Mellett, M., Frei, J., Kündig, T.M. & Pascolo, S. Protamine-Based Strategies for RNA Transfection. Pharmaceutics 13, 877 (2021).
6. Sköld, A.E. et al. Protamine-stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets. Cancer. Immunol. Immunother. 64, 1461–1473 (2015).
7. Brito, L.A. et al. A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines. Mol. Ther. 22, 2118–2129 (2014).
8. Xu, L. et al., Surface-engineered gold nanorods: promising DNA vaccine adjuvant for HIV-1 treatment. Nano. Lett. 12 (2012).
9. Tao, W. & Gill H.S. M2e-immobilized gold nanoparticles as influenza A vaccine: role of soluble M2e and longevity of protection. Vaccine 33, 2307-2315 (2015).
10. Ferrando, R.M., Lay, L. & Polito, L. Gold nanoparticle-based platforms for vaccine development. Drug Discov. Today: Technol. (2021).
11. Biddlecome, A. et al. Delivery of self-amplifying RNA vaccines in in vitro reconstituted virus-like particles. PLoS One 14, e0215031 (2019).
12. Benteyn, D., Heirman, C., Bonehill, A., Thielemans,K. & Breckpot, K. mRNA-based dendritic cell vaccines.Expert Rev. Vaccines 14, 161–176 (2015).