Arginine‐Rich Peptide‐Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide
Abstract
To date, the mRNA delivery field has been heavily dominated by lipid‐based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell‐penetrating peptide containing the amphipathic RALA motif to deliver antigen‐encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH‐dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5‐methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine‐rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.
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Peptides can also be used for mRNA delivery.
“In addition to lipid and polymer carriers, peptides can also be used for mRNA delivery.331–333”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [333]
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Wang, Z.-X., Zhang, J.-X., Wang, Y.-F., Zhou, J.-L., Jiao, X.-H., Han, M.-S., Zhang, X., Hu, H., Su, R.-X., Zhang, Y.-M., et al. (2024) · ACS Nano · doi:10.1021/acsnano.4c02400 · Cited by 49 · see citing works
Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy
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“developed a CPP containing the amphipathic RALA motif, showing a relatively high expression of antigen proteins in DC cytosol and efficient induction of potent CTL responses compared with those induced by a standard liposomal mRNA formulation (DOTAP and DOPE) [135].”
BackgroundInfluentialTockary, T. A., Abbasi, S., Matsui-Masai, M., Hayashi, A., Yoshinaga, N., Boonstra, E., Wang, Z., Fukushima, S., Kataoka, K., & Uchida, S. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214320120 · Cited by 56 · see citing works
“Previous studies showed either positive or negative effects of type I interferon on cellular immunity induction by mRNA vaccines (23, 43-46).”
BackgroundNano-bio interactions in mRNA nanomedicine: Challenges and opportunities for targeted mRNA delivery
Saiding, Q., Zhang, Z., Chen, S., Xiao, F., Chen, Y., Li, Y., Zhen, X., Khan, M. M., Chen, W., Koo, S., et al. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115116 · Cited by 57 · see citing works
Polyamine‐Mediated Stoichiometric Assembly of Ribonucleoproteins for Enhanced mRNA Delivery
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In Vivo Retargeting of Poly(beta aminoester) (OM‐PBAE) Nanoparticles is Influenced by Protein Corona
Fornaguera, C., Guerra‐Rebollo, M., Lázaro, M. Á., Cascante, A., Rubio, N., Blanco, J., & Borrós, S. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201900849 · Cited by 54 · see citing works
Potential of cell-penetrating peptides (CPPs) in delivery of antiviral therapeutics and vaccines
Sadeghian, I., Heidari, R., Sadeghian, S., Raee, M. J., & Negahdaripour, M. (2021) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2021.106094 · Cited by 54 · see citing works
McErlean, E. M., Ziminska, M., McCrudden, C. M., McBride, J. W., Loughran, S. P., Cole, G., Mulholland, E. J., Kett, V. L., Buckley, N. E., Robson, T., et al. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.11.037 · Cited by 52 · see citing works
Self-citationAn Overview of Nanoparticle-Based Delivery Platforms for mRNA Vaccines for Treating Cancer
Yang, L., Chen, X., Wang, K., Li, L., & Zhang, H. (2024) · Vaccines · doi:10.3390/vaccines12070727 · Cited by 54 · see citing works
“Repetitive arginine–alanine–leucine–alanine (RALA), a cell-penetrating peptide, possesses the capability of delivering mRNA to dendritic cells and inducing T cell-mediated immunity [100].”
BackgroundThe Potential of Cell-Penetrating Peptides for mRNA Delivery to Cancer Cells
Kim, Y., Kim, H., Kim, E. H., Jang, H., Jang, Y., Chi, S.-G., Yang, Y., & Kim, S. H. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061271 · Cited by 50 · see citing works
“found that amphipathic CPP RALA electrostatically complexed with antigen-encoding mRNA was successfully delivered to immune cells and facilitated mRNA escape from the endosomes to the cytosol, eliciting cytotoxic T cell responses [39].”
BackgroundmRNA vaccines and their delivery strategies: A journey from infectious diseases to cancer
Malla, R. R., Srilatha, M., Farran, B., & Nagaraju, G. P. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.10.024 · Cited by 48 · see citing works
Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery
Huang, P., Deng, H., Wang, C., Zhou, Y., & Chen, X. S. (2023) · Advanced Materials · doi:10.1002/adma.202307822 · Cited by 49 · see citing works
Dynamic mRNA polyplexes benefit from bioreducible cleavage sites for in vitro and in vivo transfer
Levačić, A. K., Berger, S., Müller, J., Wegner, A., Lächelt, U., Dohmen, C., Rudolph, C., & Wagner, E. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.09.016 · Cited by 47 · see citing works
mRNA delivery in cancer immunotherapy
Zhong, Y., Du, S., & Dong, Y. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.03.001 · Cited by 48 · see citing works
“Besides, pre-clinical studies involved delivering OVA, a commonly used tumor antigen, in the form of mRNA by Udhayakumar et al.(94) using cell-penetrating peptide nanocomplexes.”
MethodEngineered mRNA Delivery Systems for Biomedical Applications
Wang, J., Zhu, H., Gan, J., Liang, G., Li, L., & Zhao, Y. (2023) · Advanced Materials · doi:10.1002/adma.202308029 · Cited by 44 · see citing works
Scope and challenges of nanoparticle-based mRNA delivery in cancer treatment
Karim, M. E., Haque, S. T., Al-Busaidi, H., Bakhtiar, A., Tha, K. K., Holl, M. M. B., & Chowdhury, E. H. (2022) · Archives of Pharmacal Research · doi:10.1007/s12272-022-01418-x · Cited by 42 · see citing works
Natural peptides for immunological regulation in cancer therapy: Mechanism, facts and perspectives
Zhang, Y., Liu, C., Wu, C., & Song, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114257 · Cited by 43 · see citing works
Protein-based delivery systems for RNA delivery
Zhu, H., Luo, H., Chang, R., Yang, Y., Liu, D., Ji, Y. R., Qin, H., Rong, H., & Yin, J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.09.032 · Cited by 39 · see citing works
McCrudden, C. M., McBride, J. W., McCaffrey, J., McErlean, E. M., Dunne, N., Kett, V. L., Coulter, J. A., Robson, T., & McCarthy, H. O. (2018) · Cancer Nanotechnology · doi:10.1186/s12645-018-0040-x · Cited by 39 · see citing works
Self-citationPolylactide-Based Reactive Micelles as a Robust Platform for mRNA Delivery
Lacroix, C., Humanes, A., Coiffier, C., Gigmès, D., Verrier, B., & Trimaille, T. (2020) · Pharmaceutical Research · doi:10.1007/s11095-019-2749-6 · Cited by 39 · see citing works
“have studied RALA complexed with eGFP and ovalbumin mRNAs in a vaccine context but their serum stability were not investigated either [47].”
BackgroundNanoformulations targeting immune cells for cancer therapy: mRNA therapeutics
Yang, W., Cao, J., Cheng, H., Chen, L., Yu, M., Chen, Y., & Cui, X. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.11.014 · Cited by 36 · see citing works
“In this context, CD8 + CTLs at a low level might be involved in the early control on viral infections prior to the production of sufficient antibodies.”
InfluentialThe potential of nanoparticle vaccines as a treatment for cancer
Urbanavicius, D. B., Alvarez, T., Such, G. K., Johnston, A. P. R., & Mintern, J. D. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2017.12.022 · Cited by 34 · see citing works
The Current Landscape of mRNA Vaccines Against Viruses and Cancer–A Mini Review
Ladak, R. J., He, A. J., Huang, Y.-H., & Ding, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.885371 · Cited by 33 · see citing works
“This method is exemplified when this delivery system was used to successfully transfect DCs in vitro, and induce T cell-mediated immunity in vivo (86).”
MethodNutrients Interaction with the Immune System.
Noor, S., Piscopo, S., & Gasmi, A. (2021) · PubMed Central · doi:10.22092/ari.2021.356098.1775 · Cited by 38 · see citing works
“derived compounds and arginine-rich peptide-based messenger ribonucleic acid nanoparticles have been successfully used to enhance cytotoxic T cells immunity (34).”
MethodNovel Vectors and Administrations for mRNA Delivery
Bai, C., Wang, C., & Lu, Y. (2023) · Small · doi:10.1002/smll.202303713 · Cited by 32 · see citing works
Bioinspired Spatiotemporal Management toward RNA Therapies
Ma, Y., Li, S., Lin, X., & Chen, Y. (2023) · ACS Nano · doi:10.1021/acsnano.3c08219 · Cited by 32 · see citing works
Layer-by-Layer technique as a versatile tool for gene delivery applications
Linnik, D., Tarakanchikova, Y. V., Zyuzin, M. V., Lepik, K. V., Aerts, J. L., Sukhorukov, G. B., & Timin, A. S. (2021) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2021.1879790 · Cited by 32 · see citing works
“ods show low transfection efficiency [104]; some have higher efficiency, but also show high toxicity [105]; some are difficult to produce [106].”
BackgroundSpray drying: Inhalable powders for pulmonary gene therapy
Munir, M., Jena, L., Kett, V. L., Dunne, N., & McCarthy, H. O. (2021) · Biomaterials Advances · doi:10.1016/j.msec.2021.112601 · Cited by 32 · see citing works
Self-citationBouazzaoui, A., & Abdellatif, A. A. H. (2024) · Vaccine X · doi:10.1016/j.jvacx.2024.100500 · Cited by 29 · see citing works
“In another work, the research group used hydrophobic alanine (Ala) and leucine (Leu) residues, and cationic arginine to develop mRNA vaccines [161].”
BackgroundStrategies to deliver RNA by nanoparticles for therapeutic potential
Cox, A., Lim, S. A., & Chung, E. J. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100991 · Cited by 27 · see citing works
Lü, Y., Tang, L., Zhang, M., & Liu, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.896958 · Cited by 27 · see citing works
“Protamine complexed with mRNA can not only protect mRNA from degradation by RNase in serum (104) but also act as an adjuvant.”
BackgroundBhosle, S. M., Loomis, K. H., Kirschman, J. L., Blanchard, E. L., Vanover, D. A., Zurla, C., Habrant, D., Edwards, D., Baumhof, P., Pitard, B., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.01.010 · Cited by 24 · see citing works
“The next day, the label ed IVT mRNA was filtered using a 200 kD MWCO ultrafiltration unit (Advantec MFS Inc) to remove unbound MTRIPs and concentrated by 30 kD MWCO centrifugal filters [39,64]”
MethodSelf-citationIn the Era of mRNA Vaccines, Is There Any Hope for HIV Functional Cure?
Esteban, I., Pastor-Quiñones, C., Usero, L., Plana, M., García, F., & Leal, L. (2021) · Viruses · doi:10.3390/v13030501 · Cited by 26 · see citing works
“The chemical nature of those carriers is diverse, lipidic [44,55], polymeric [56], peptidic [57], or a combination of them [58].”
BackgroundAdvancing Cancer Immunotherapy: The Potential of mRNA Vaccines As a Promising Therapeutic Approach
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Nanoparticle-based delivery platforms for mRNA vaccine development
Okay, S., Özcan, Ö. Ö., & Karahan, M. (2020) · AIMS Biophysics · doi:10.3934/biophy.2020023 · Cited by 23 · see citing works
“Arginine-rich RALA peptide (WEARLARALARALARHLARALARALRACEA) was used to obtain a condensed nanocomplex with OVA-mRNA, providing specific CTL response in mice [75].”
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Interaction design in mRNA delivery systems
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mRNA delivery technologies: Toward clinical translation
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“Later, cationic cellpenetrating peptides such as RALA [47], KALA [48] and PepFect14 [49] were developed to improve the delivery efficiency.”
BackgroundThe main battlefield of mRNA vaccine – Tumor immune microenvironment
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RetractedPeptide-Based Nanoparticles for Systemic Extrahepatic Delivery of Therapeutic Nucleotides
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“Among various delivery systems, including polymers [9–12], exosomes [13–15], inorganic nanoparticles [16, 17], and peptides [18], Lipid nanoparticles (LNPs) stand out as the only carriers with regulatory approval for mRNA [19, 20].”
BackgroundOff the beaten path: Novel mRNA-nanoformulations for therapeutic vaccination against HIV
D’haese, S., Lacroix, C., García, F., Plana, M., Ruță, S. M., Vanham, G. L., Verrier, B., & Aerts, J. L. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.11.009 · Cited by 18 · see citing works
- Authors
- Udhayakumar, V. K., De Beuckelaer, A., McCaffrey, J., McCrudden, C. M., Kirschman, J. L., Vanover, D., Van Hoecke, L., Roose, K., Deswarte, K., De Geest, B. G., Lienenklaus, S., Santangelo, P. J., Grooten, J., McCarthy, H. O., & De Koker, S.
- Affiliations
- Ghent University (BE)
- Department of Biomedical Molecular Biology Ghent University 9052 Ghent Belgium
- Queen's University Belfast (GB)
- Georgia Institute of Technology (US)
- Ghent University Hospital (BE)
- Biopharmaceutical Technology Unit Ghent University 9052 Ghent Belgium
- Helmholtz Centre for Infection Research (DE)
- Corresponding author
- Grooten, Johan
- ORCID
- Venue
- Advanced Healthcare Materials
- Publisher
- Wiley
- Published
- 2017-04-24
- Volume
- 6
- Issue
- 13
- ISSN
- 2192-2640 (ISSN-L)
- 2192-2659
- OpenAlex
- W2607579286
- Cited by
- 169
- References
- 23
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 27 · 2023: 34 · 2022: 30 · 2021: 24 · 2020: 16 · 2019: 6 · 2018: 7 · 2017: 3
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Advanced Healthcare Materials (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Defense Advanced Research Projects Agency (W911NF‐11‐2‐0068)
- Fonds Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- arginine-rich peptides, peptide amphiphiles, cell-penetrating peptides, mRNA delivery, mRNA vaccines, dendritic cells, endosomal escape, pseudouridine, 5-methylcytidine, cellular uptake
- MeSH terms
- Animals, Antigens, Cytoplasm, Female, Endosomes, RNA, Messenger, Drug Delivery Systems, Mice, Knockout, CD8-Positive T-Lymphocytes, Amino Acid Motifs, Nanostructures, Mice, Cell-Penetrating Peptides
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