Protamine-Based Strategies for RNA Transfection
Open accessPublished version of a preprint
Abstract
Protamine is a natural cationic peptide mixture mostly known as a drug for the neutralization of heparin and as a compound in formulations of slow-release insulin. Protamine is also used for cellular delivery of nucleic acids due to opposite charge-driven coupling. This year marks 60 years since the first use of Protamine as a transfection enhancement agent. Since then, Protamine has been broadly used as a stabilization agent for RNA delivery. It has also been involved in several compositions for RNA-based vaccinations in clinical development. Protamine stabilization of RNA shows double functionality: it not only protects RNA from degradation within biological systems, but also enhances penetration into cells. A Protamine-based RNA delivery system is a flexible and versatile platform that can be adjusted according to therapeutic goals: fused with targeting antibodies for precise delivery, digested into a cell penetrating peptide for better transfection efficiency or not-covalently mixed with functional polymers. This manuscript gives an overview of the strategies employed in protamine-based RNA delivery, including the optimization of the nucleic acid’s stability and translational efficiency, as well as the regulation of its immunostimulatory properties from early studies to recent developments.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Specific immune responses against at least one antigen were detected in 63% of patients after treatment, and the frequency of activated IgD+ CD38hi B cells increased by more than two-fold in 60% of evaluated patients.
“Specific immune responses against at least one antigen were detected in 63% of patients after treatment, and the frequency of activated IgD+ CD38hi B cells increased by more than two-fold in 60% of evaluated patients.343,353,354”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [354]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429 · see citing works
Biochemical and Biophysical Research Communications
Rc, A. N., On Filamentous Bacteriophage, M., Hoffmann, S., & Willbold, D. (1960) · Nature · doi:10.1038/186124d0 · Cited by 6,690 · see citing works
Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., & Reis e Sousa, C. (2004) · Science · doi:10.1126/science.1093616 · Cited by 3,444 · see citing works
Non-viral vectors for gene-based therapy
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3763 · Cited by 3,123 · see citing works
Knocking down barriers: advances in siRNA delivery
Whitehead, K. A., Langer, R., & Anderson, D. G. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2742 · Cited by 3,115 · see citing works
Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681 · see citing works
Nanocarriers’ entry into the cell: relevance to drug delivery
Hillaireau, H., & Couvreur, P. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0053-z · Cited by 1,549 · see citing works
Iversen, T., Skotland, T., & Sandvig, K. (2011) · Nano Today · doi:10.1016/j.nantod.2011.02.003 · Cited by 1,235 · see citing works
Ashwell, G., & Morell, A. G. (1974) · Advances in enzymology and related areas of molecular biology/Advances in enzymology and related subjects · doi:10.1002/9780470122860.ch3 · Cited by 1,212 · see citing works
Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors
Song, E., Zhu, P., Lee, S., Chowdhury, D., Kussman, S., Dykxhoorn, D. M., Feng, Y., Palliser, D., Weiner, D. B., Shankar, P., et al. (2005) · Nature Biotechnology · doi:10.1038/nbt1101 · Cited by 1,022 · see citing works
Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J., & Allison, J. P. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20082492 · Cited by 967 · see citing works
Cantón, I., & Battaglia, G. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15309b · Cited by 940 · see citing works
Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.
Boczkowski, D., Nair, S. K., Snyder, D., & Gilboa, E. (1996) · The Journal of experimental medicine · doi:10.1084/jem.184.2.465 · Cited by 915 · see citing works
Nanoparticle-Aptamer Bioconjugates
Farokhzad, O. C., Jon, S., Khademhosseini, A., Tran, T.-N., LaVan, D. A., & Langer, R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2550 · Cited by 897 · see citing works
Alberer, M., Gnad-Vogt, U., Hong, H. S., Mehr, K. T., Backert, L., Finak, G., Gottardo, R., Bica, M. A., Garofano, A., Koch, S. D., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31665-3 · Cited by 530 · see citing works
In vivo gene transfer via intravenous administration of cationic lipid–protamine–DNA (LPD) complexes
Li, S., & Huang, L. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300482 · Cited by 478 · see citing works
Potentiation of Cationic Liposome-Mediated Gene Delivery by Polycations
Gao, X., & Huang, L. (1996) · Biochemistry · doi:10.1021/bi952436a · Cited by 461 · see citing works
Protamine sulfate enhances lipid-mediated gene transfer
Sorgi, F., Bhattacharya, S. S., & Huang, L. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300484 · Cited by 453 · see citing works
siRNA Delivery Strategies: A Comprehensive Review of Recent Developments
Tatiparti, K., Sau, S., Kashaw, S. K., & Iyer, A. K. (2017) · Nanomaterials · doi:10.3390/nano7040077 · Cited by 429 · see citing works
Materials for non-viral intracellular delivery of messenger RNA therapeutics
Kauffman, K. J., Webber, M. J., & Anderson, D. G. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.12.032 · Cited by 400 · see citing works
Weide, B., Pascolo, S., Scheel, B., Derhovanessian, E., Pflugfelder, A., Eigentler, T. K., Pawelec, G., Hoerr, I., Rammensee, H.-G., & Garbe, C. (2009) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181a00068 · Cited by 378 · cited 3× · see citing works
“Just after the evaluation of naked mRNA vaccine in melanoma patients [48], the Tuebingen-based research group explored Protamine-mRNA complexes in a Phase I/II vaccination trial in metastatic melanoma patients (NCT00204607) [42].”
BackgroundMethodSelf-citationCharacterization of cationic lipid-protamine–DNA (LPD) complexes for intravenous gene delivery
Li, S., Rizzo, M., Bhattacharya, S. S., & Huang, L. (1998) · Gene Therapy · doi:10.1038/sj.gt.3300683 · Cited by 369 · see citing works
The Silent Revolution: RNA Interference as Basic Biology, Research Tool, and Therapeutic
Dykxhoorn, D. M., & Lieberman, J. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104606 · Cited by 338 · see citing works
Fotin-Mleczek, M., Duchardt, K. M., Lorenz, C., Pfeiffer, R., Ojkić-Zrna, S., Probst, J., & Kallen, K.-J. (2011) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181f7dbe8 · Cited by 335 · cited 1× · see citing works
“Fotin-Mleczek and colleagues explored another aspect of immunostimulatory RNA formulations for cancer immunotherapy [40].”
BackgroundEnhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics
Lönn, P., Kacsinta, A. D., Cui, X.-S., Hamil, A. S., Kaulich, M., Gogoi, K., & Dowdy, S. F. (2016) · Scientific Reports · doi:10.1038/srep32301 · Cited by 325 · see citing works
Kübler, H., Scheel, B., Gnad-Vogt, U., Miller, K., Schultze-Seemann, W., vom Dorp, F., Parmiani, G., Hampel, C., Wedel, S., Trojan, L., et al. (2015) · Journal for Immunotherapy of Cancer · doi:10.1186/s40425-015-0068-y · Cited by 287 · see citing works
Peer, D., Zhu, P., Carman, C. V., Lieberman, J., & Shimaoka, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608491104 · Cited by 276 · see citing works
Intracellular Fate of Spherical Nucleic Acid Nanoparticle Conjugates
Wu, X. A., Choi, C. H. J., Zhang, C., Hao, L., & Mirkin, C. A. (2014) · Journal of the American Chemical Society · doi:10.1021/ja503010a · Cited by 245 · see citing works
Papachristofilou, A., Hipp, M., Klinkhardt, U., Früh, M., Sebastian, M., Weiß, C., Pless, M., Cathomas, R. L., Hilbe, W., Pall, G., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0520-5 · Cited by 228 · see citing works
Interfacing Materials Science and Biology for Drug Carrier Design
Such, G. K., Yan, Y., Johnston, A. P. R., Gunawan, S. T., & Caruso, F. (2015) · Advanced Materials · doi:10.1002/adma.201405084 · Cited by 219 · see citing works
Cuellar, T. L., Barnes, D., Nelson, C., Tanguay, J., Yu, S., Wen, X., Scales, S. J., Gesch, J., Davis, D., Smith, A. V. B., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1362 · Cited by 215 · see citing works
Sebastian, M., Schröder, A., Scheel, B., Hong, H. S., Muth, A., von Boehmer, L., Zippelius, A., Mayer, F., Reck, M., Atanackovic, D., et al. (2019) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-019-02315-x · Cited by 209 · see citing works
Scheel, B., Teufel, R., Probst, J., Carralot, J., Geginat, J., Radsak, M. P., Jarrossay, D., Wagner, H., Jung, G., Rammensee, H., et al. (2005) · European Journal of Immunology · doi:10.1002/eji.200425656 · Cited by 198 · see citing works
Self-citationTargeted Delivery of PLK1-siRNA by ScFv Suppresses Her2 + Breast Cancer Growth and Metastasis
Yao, Y., Sun, T., Huang, S., Dou, S., Lin, L., Chen, J.-N., Ruan, J.-B., Mao, C., Yu, F., Zeng, M., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003601 · Cited by 189 · see citing works
pH-Dependent complexation of poly(acrylic acid) derivatives with phospholipid vesicle membranes
Seki, K., & Tirrell, D. A. (1984) · Macromolecules · doi:10.1021/ma00139a009 · Cited by 172 · see citing works
Warrant, R. W., & Kim, S. (1978) · Nature · doi:10.1038/271130a0 · Cited by 161 · see citing works
Essential Role of Histone Replacement and Modifications in Male Fertility
Wang, T., Gao, H., Li, W., & Liu, C. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00962 · Cited by 160 · see citing works
Seok, H. Y., Rejinold, N. S., Lekshmi, K. M., Cherukula, K., Park, I., & Kim, Y. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.04.050 · Cited by 152 · see citing works
Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy
Yuba, E., Tajima, N., Yoshizaki, Y., Harada, A., Hayashi, H., & Kono, K. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2013.12.024 · Cited by 141 · see citing works
Immunostimulating capacities of stabilized RNA molecules
Scheel, B., Braedel, S., Probst, J., Carralot, J., Wagner, H., Schild, H., Jung, G., Rammensee, H., & Pascolo, S. (2004) · European Journal of Immunology · doi:10.1002/eji.200324198 · Cited by 138 · see citing works
Self-citationThe systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine
Choi, Y.-S., Lee, J. Y., Suh, J. S., Kwon, Y. M., Lee, S. J., Chung, J.-K., Lee, D.-S., Yang, V. C.-M., Chung, C., & Park, Y. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.11.001 · Cited by 127 · see citing works
Small liposomes are better than large liposomes for specific drug delivery in vitro
Machy, P., & Leserman, L. (1983) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(83)90348-6 · Cited by 122 · see citing works
Zhang, W., Xu, W., Lan, Y., He, X., Liu, K., & Liang, Y. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s203113 · Cited by 122 · see citing works
Park, Y. J., Chang, L., Liang, J. F., Moon, C., Chung, C., & Yang, V. C.-M. (2005) · The FASEB Journal · doi:10.1096/fj.04-2322fje · Cited by 116 · see citing works
Protamines. Isolation, Characterization, Structure and Function.
Ando, T., Yamasaki, M., & Suzuki, K. (1974) · Annals of Internal Medicine · doi:10.7326/0003-4819-81-1-143_5 · Cited by 109 · see citing works
Particle size and activation threshold: a new dimension of danger signaling
Rettig, L., Haen, S. P., Bittermann, A. G., von Boehmer, L., Fontecedro, A. C., Krämer, S. D., Knuth, A. K., & Pascolo, S. (2010) · Blood · doi:10.1182/blood-2009-11-247817 · Cited by 108 · see citing works
Self-citationTherapeutic anti‐tumor immunity triggered by injections of immunostimulating single‐stranded RNA
Scheel, B., Aulwurm, S., Probst, J., Stitz, L., Hoerr, I., Rammensee, H., Weller, M., & Pascolo, S. (2006) · European Journal of Immunology · doi:10.1002/eji.200635910 · Cited by 108 · see citing works
Self-citationFotin‐Mleczek, M., Zanzinger, K., Heidenreich, R., Lorenz, C., Thess, A., Duchardt, K. M., & Kallen, K. (2012) · The Journal of Gene Medicine · doi:10.1002/jgm.2605 · Cited by 103 · see citing works
Delgado, D., del Pozo‐Rodríguez, A., Solinís, M. Á., & Rodríguez‐Gascón, A. (2011) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2011.06.005 · Cited by 101 · see citing works
Protamine as an Efficient Membrane-Translocating Peptide
Reynolds, F., Weissleder, R., & Josephson, L. (2005) · Bioconjugate Chemistry · doi:10.1021/bc0501451 · Cited by 100 · see citing works
Hybrid Biopolymer and Lipid Nanoparticles with Improved Transfection Efficacy for mRNA
Siewert, C. D., Haas, H., Cornet, V., Nogueira, S. S., Nawroth, T., Uebbing, L., Ziller, A., Al-Gousous, J., Rădulescu, A., Schroer, M. A., et al. (2020) · Cells · doi:10.3390/cells9092034 · Cited by 89 · see citing works
Wu, J., Liu, P., Zhu, J.-L., Maddukuri, S., & Zern, M. Α. (1998) · Hepatology · doi:10.1002/hep.510270319 · Cited by 82 · see citing works
Increased receptor-mediated gene delivery to the liver by protamine-enhanced-asialofetuin-lipoplexes
Arangoa, M. A., Düzgüneş, N., & de Ilarduya, C. T. (2003) · Gene Therapy · doi:10.1038/sj.gt.3301840 · Cited by 80 · see citing works
Wang, S., Cao, M., Deng, X., Xiao, X., Yin, Z., Hu, Q., Zhou, Z., Zhang, F., Zhang, R., Wu, Y. F., et al. (2014) · Advanced Healthcare Materials · doi:10.1002/adhm.201400222 · Cited by 78 · see citing works
Protamine enhancement of RNA uptake by cultured chick cells
Amos, H. (1961) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(61)90069-9 · Cited by 75 · see citing works
Ando, T., Yamasaki, M., & Suzuki, K. (1973) · Molecular biology, biochemistry, and biophysics · doi:10.1007/978-3-642-46294-8 · Cited by 70 · see citing works
RNActive® Technology: Generation and Testing of Stable and Immunogenic mRNA Vaccines
Rauch, S., Lutz, J., Kowalczyk, A., Schlake, T., & Heidenreich, R. (2017) · Methods in Molecular Biology · doi:10.1007/978-1-4939-6481-9_5 · Cited by 57 · see citing works
Zhong, L., Liu, Y., Xu, L., Li, Q., Zhao, D., Li, Z., Zhang, H., Zhang, H., Kan, Q., Sun, J., et al. (2018) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2018.11.002 · Cited by 56 · see citing works
Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy
Dou, S., Yao, Y., Yang, X., Sun, T., Mao, C., Song, E., & Wang, J. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.05.015 · Cited by 52 · see citing works
Antibody-coupled siRNA as an efficient method for in vivo mRNA knockdown
Bäumer, N., Appel, N., Terheyden, L., Buchholz, F., Rössig, C., Müller‐Tidow, C., Berdel, W. E., & Bäumer, S. (2015) · Nature Protocols · doi:10.1038/nprot.2015.137 · Cited by 52 · see citing works
Aptamer-protamine-siRNA nanoparticles in targeted therapy of ErbB3 positive breast cancer cells
Xu, X. S., Li, L., Li, X., Tao, D., Zhang, P., & Gong, J. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119963 · Cited by 43 · see citing works
Functional differences between protamine preparations for the transfection of mRNA
Jarzębska, N. T., Läuchli, S., Iselin, C., French, L. E., Johansen, P., Guenova, E., Kündig, T. M., & Pascolo, S. (2020) · Drug Delivery · doi:10.1080/10717544.2020.1790692 · Cited by 42 · see citing works
Self-citationThe role of peptide-based therapeutics in oncotherapy
Timur, S. S., & Gürsoy, R. N. (2021) · Journal of drug targeting · doi:10.1080/1061186x.2021.1906884 · Cited by 40 · see citing works
Liu, J., Guo, S., Li, Z., Liu, L., & Gu, J. (2009) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2009.04.026 · Cited by 33 · see citing works
Exploring cell type-specific internalizing antibodies for targeted delivery of siRNA
Liu, B. (2007) · Briefings in Functional Genomics and Proteomics · doi:10.1093/bfgp/elm015 · Cited by 30 · see citing works
The use of basic proteins to increase the infectivity of enterovirus ribonucleic acid
Smull, C. E., Mallette, M. F., & LUDWIG, E. H. (1961) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(61)90155-3 · Cited by 29 · see citing works
From discovering to understanding
Dahm, R. (2010) · EMBO Reports · doi:10.1038/embor.2010.14 · Cited by 28 · see citing works
Vighi, E., Montanari, M., Ruozi, B., Tosi, G., Magli, A., & Leo, E. (2010) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2010.07.012 · Cited by 27 · see citing works
Aptamer-Equipped Protamine Nanomedicine for Precision Lymphoma Therapy
Zeng, Z., Tung, C., & Zu, Y. (2020) · Cancers · doi:10.3390/cancers12040780 · Cited by 27 · see citing works
Generation of Immunostimulating 130 nm Protamine–RNA nanoparticles
Tusup, M., & Pascolo, S. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6481-9_9 · Cited by 15 · see citing works
Self-citationDendritic cells loaded with CD44+ CT‑26 colon cell lysate evoke potent antitumor immune responses
Fu, C., Zhou, N., Zhao, Y., Duan, J., Xu, H., & Wang, Y. (2019) · Oncology Letters · doi:10.3892/ol.2019.10952 · Cited by 12 · see citing works
Hoerr, I. (2000) · doi:10.1002/1521-4141(200001)30:1
Flagged first, then by citations
3 of the 75 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Therapeutic cancer vaccines: Advancements, challenges, and prospects
Fan, T., Zhang, M., Yang, J., Zhu, Z., Cao, W., & Dong, C. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01674-3 · Cited by 597 · see citing works
Advances in COVID-19 mRNA vaccine development
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00950-y · Cited by 601 · see citing works
Polymer‐Based mRNA Delivery Strategies for Advanced Therapies
Yang, W., Mixich, L., Boonstra, E., & Cabral, H. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202202688 · Cited by 190 · see citing works
Recent Advances in Lipid Nanoparticles for Delivery of mRNA
Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F. H., Zhang, Z., Li, Y., & Huang, W. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122682 · Cited by 178 · see citing works
Recent Advancement in mRNA Vaccine Development and Applications
Fayez, N. A., Nassar, M. S., Alshehri, A. A., Alnefaie, M. K., Almughem, F. A., Alshehri, B. Y., Alawad, A. O., & Tawfik, E. A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15071972 · Cited by 177 · see citing works
Cationic Polymers as Transfection Reagents for Nucleic Acid Delivery
Cai, X., Dou, R., Guo, C., Tang, J., Li, X., Chen, J., & Zhang, J. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15051502 · Cited by 136 · see citing works
RNA therapeutics in the clinic
Curreri, A. M., Sankholkar, D., Mitragotri, S., & Zhao, Z. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10374 · Cited by 96 · see citing works
mRNA-Based Vaccines and Therapeutics for COVID-19 and Future Pandemics
Chavda, V. P., Soni, S., Vora, L. K., Soni, S., Khadela, A. D., & Ajabiya, J. (2022) · Vaccines · doi:10.3390/vaccines10122150 · Cited by 82 · see citing works
Current state of the art in peptide-based gene delivery
Hadianamrei, R., & Zhao, X. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.010 · Cited by 78 · see citing works
Jia, W., Wu, Y., Xie, Y., Yu, M., & Chen, Y. (2025) · Advanced Materials · doi:10.1002/adma.202413603 · Cited by 74 · see citing works
Zhou, W., Jiang, L., Liao, S., Wu, F., Yang, G., Hou, L., Liu, L., Pan, X., Jia, W. W.-G., & Zhang, Y. (2023) · Viruses · doi:10.3390/v15081760 · Cited by 62 · see citing works
Xu, L., Cao, Y., Ya, X., Li, R., & Xu, X. (2023) · Macromolecular Bioscience · doi:10.1002/mabi.202300238 · Cited by 53 · see citing works
An 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
mRNA vaccines in the prevention and treatment of diseases
Gu, Y., Duan, J., Yang, N., Yang, Y., & Zhao, X. (2022) · MedComm · doi:10.1002/mco2.167 · Cited by 51 · see citing works
Advancements in monkeypox vaccines development: a critical review of emerging technologies
Garcia-Atutxa, I., Mondragón‐Terán, P., Saquero, A. H., & Villanueva‐Flores, F. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1456060 · Cited by 43 · see citing works
Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials
Karimi-Sani, I., Molavi, Z., Naderi, S., Mirmajidi, S. H., Zare, I., Naeimzadeh, Y., Mansouri, A., Tajbakhsh, A., Savardashtaki, A., & Sahebkar, A. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02882-x · Cited by 38 · see citing works
Umar, A. K., Limpikirati, P. K., Rivai, B., Ardiansah, I., Sriwidodo, S., & Luckanagul, J. A. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e41246 · Cited by 25 · see citing works
Advances in Engineering Circular RNA Vaccines
Zhang, Z., Fu, Y., Ju, X., Zhang, F., Zhang, P., & He, M. (2024) · Pathogens · doi:10.3390/pathogens13080692 · Cited by 24 · see citing works
Lu, Y., Qian, C., Huang, Y., Ren, T., Xie, W., Xia, N., & Li, S. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.145501 · Cited by 26 · see citing works
Interaction design in mRNA delivery systems
Yu, M., Lin, L., Zhou, D., & Liu, S. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.11.038 · Cited by 23 · see citing works
González-García, D., Tapia, O., Évora, C., García‐García, P., & Delgado, A. (2024) · Drug Delivery and Translational Research · doi:10.1007/s13346-024-01644-4 · Cited by 21 · see citing works
Cancer mRNA vaccines: clinical application progress and challenges
Li, H., Min, L., Du, H., Wei, X., & Tong, A. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217752 · Cited by 24 · see citing works
Nonviral targeted mRNA delivery: principles, progresses, and challenges
He, X., Li, G., Huang, L., Shi, H., Zhong, S., Zhao, S., Jiao, X., Xin, J., Yin, X., Liu, S., et al. (2025) · MedComm · doi:10.1002/mco2.70035 · Cited by 20 · see citing works
Progress and Challenges of Messenger RNA Vaccines in the Therapeutics of NSCLC
Kiousi, E., Lyraraki, V., Mardiki, G. L., Stachika, N., Damianou, A. K., Malainou, C. P., Syrigos, N. K., Gomatou, G., & Kotteas, E. A. (2023) · Cancers · doi:10.3390/cancers15235589 · Cited by 20 · see citing works
Ansari, A. S., Remant, K. C., Morales, L. C., Nasrullah, M., Sundaram, D. N. M., Kucharski, C., Jiang, X., Brandwein, J. M., & Uludağ, H. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.02.018 · Cited by 19 · see citing works
Gu, J., Xu, Z., Liu, Q., Tang, S., Zhang, W., Xie, S., Chen, X., Chen, J., Yong, K., Yang, C., et al. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302409 · Cited by 19 · see citing works
Delivery of mRNA for cancer therapy: progress and prospects
Su, L.-J., Xu, M.-X., Ji, Z.-H., Zhu, J.-Q., Yu, M., Wang, Y., & Lin, Y. (2023) · Nano Today · doi:10.1016/j.nantod.2023.102013 · Cited by 17 · see citing works
Wang, J., Huang, S., Wei, H., Liang, S., Ding, Y., Xiao, Z., & Shuai, X. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.04.039 · Cited by 16 · see citing works
Utilizing chemotherapy-induced tumor RNA nanoparticles to improve cancer chemoimmunotherapy
Su, L., Pan, W., Li, X., Zhou, X., Ma, X., & Min, Y. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.12.039 · Cited by 16 · see citing works
Mohanty, P., Panda, P., Acharya, R. K., Pande, B., Bhaskar, L. V., & Verma, H. K. (2023) · World Journal of Virology · doi:10.5501/wjv.v12.i5.242 · Cited by 17 · see citing works
Faust, A., Bäumer, N., Schlütermann, A., Becht, M., Greune, L., Geyer, C., Rüter, C., Margeta, R., Wittmann, L., Dersch, P., et al. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202109769 · Cited by 14 · see citing works
Peptides: potential delivery systems for mRNA
Liang, H., Xing, Y., Wang, K., Zhang, Y., Yin, F., & Li, Z. (2025) · RSC Chemical Biology · doi:10.1039/d4cb00295d · Cited by 14 · see citing works
Therapeutic application of extracellular vesicles in human diseases
Nunes, A., Zhang, T., Mu, X., & Robbins, P. D. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.002 · Cited by 14 · see citing works
An efficient mRNA delivery system for genome editing in plants
Qiu, F., Xue, C., Liu, J., Li, B., Gao, Q., Liang, R., Chen, K., & Gao, C. (2025) · Plant Biotechnology Journal · doi:10.1111/pbi.14591 · Cited by 15 · see citing works
Recent Advances in mRNA Delivery Systems for Cancer Therapy
Zhang, Z., Fan, Y., Jiang, S., Ma, Y., Yu, Y., Qing, Y., Li, Q., Liu, Y., Shen, S., & Wang, J. (2025) · Advanced Science · doi:10.1002/advs.202417571 · Cited by 14 · see citing works
Jang, Y. H., Raspaud, É., & Lansac, Y. (2023) · Nanoscale Advances · doi:10.1039/d2na00847e · Cited by 12 · see citing works
Cellular uptake and trafficking of peptide-based drug delivery systems for miRNA
Ruseska, I., & Zimmer, A. (2023) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2023.08.019 · Cited by 12 · see citing works
Protamine—The Journey from DNA to Heparin Neutralization to Gene therapy
Thachil, J. V. (2021) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0041-1736574 · Cited by 10 · see citing works
Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases
Gurung, S., Perocheau, D. P. B., Ghosh, R., Hart, S. L., & Baruteau, J. (2025) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70078 · Cited by 8 · see citing works
Sioud, M. (2023) · Scandinavian Journal of Immunology · doi:10.1111/sji.13282 · Cited by 7 · see citing works
Hu, H., Yuan, T., Qian, J., Lu, X., Chen, X., Sun, X., Lin, Y., Tang, Y., Xu, Q., Zhu, T., et al. (2024) · European Polymer Journal · doi:10.1016/j.eurpolymj.2024.112871 · Cited by 7 · see citing works
Garge, S. Y., Suvarna, V., Sonavane, S. V., & Singh, P. K. (2025) · ACS Applied Bio Materials · doi:10.1021/acsabm.5c01343 · Cited by 7 · see citing works
Watanabe, T., Ochi, Y., Kajihara, R., Ichikawa, K., Ezaki, R., Matsuzaki, M., & Horiuchi, H. (2023) · Biotechnology Journal · doi:10.1002/biot.202300328 · Cited by 7 · see citing works
Advances in Therapeutic Cancer Vaccines, Their Obstacles, and Prospects Toward Tumor Immunotherapy
Eskandari, A., Leow, T. C., Rahman, M. B. A., & Oslan, S. N. (2024) · Molecular Biotechnology · doi:10.1007/s12033-024-01144-3 · Cited by 7 · see citing works
Non‐Viral Nucleic Acid Delivery System for RNA Therapeutics
Liu, L., Zhou, Y., Xu, A., Wang, C., Li, N., Huang, H., Zhang, Y., & Yang, X. (2023) · Advanced Therapeutics · doi:10.1002/adtp.202300005 · Cited by 7 · see citing works
Lipid-free, thermostable mRNA vaccines prepared using atomic layer deposition
Coleman, H. J., Rauch, A., Langsfeld, E. S., Anderson, K. M., Parlikar, U. R., Funke, H. H., Garcea, R. L., & Randolph, T. W. (2025) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2025.104066 · Cited by 6 · see citing works
Liao, X., Han, D., Qi, L.-J., Huang, Q.-Y., Gao, Q.-Y., He, X., Guo, T., Lei, J.-J., & Cheng, S. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114542 · Cited by 6 · see citing works
Harnessing RNA molecules for therapy: advances in design, delivery, and clinical development
Zou, J., He, X., Li, Z., Song, B., Xing, X., Yu, J., & He, W. (2025) · Targetome · doi:10.48130/targetome-0025-0003 · Cited by 6 · see citing works
Laturski, A. E., Dulay, M. T., Perry, J. L., & DeSimone, J. M. (2025) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.5c00028 · Cited by 6 · see citing works
Delivery Systems of Plasmid DNA and Messenger RNA for Advanced Therapies
Uchida, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14040810 · Cited by 6 · see citing works
Pascolo, S. (2023) · European Journal of Immunology · doi:10.1002/eji.202249941 · Cited by 6 · see citing works
Self-citationNext‐Generation Nonviral Vectors for mRNA Vaccine Delivery
Chen, M., Hu, X., & Liu, S. (2022) · Macromolecular Chemistry and Physics · doi:10.1002/macp.202100443 · Cited by 5 · see citing works
Environment‐Responsive Peptide Dimers Bind and Stabilize Double‐Stranded RNA
McLoughlin, N. M., Albers, M. A., Camps, E. C., Paulus, J., Ran, Y. A., Neubacher, S., Hennig, S., Brock, R. E., & Grossmann, T. N. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202308028 · Cited by 5 · see citing works
Recent advances in engineering approaches for delivery of mRNA-based therapeutics
Prinindya, K. N. N., Ashraf, G. M., Uddin, S., Mahdi, E., & Hasan, A. (2025) · Biomaterials Advances · doi:10.1016/j.bioadv.2025.214667 · Cited by 5 · see citing works
Pulmonary Delivery for miRs: Present and Future Potential
Shrestha, A., Haque, M. A., & Mattheolabakis, G. (2023) · Processes · doi:10.3390/pr11061788 · Cited by 4 · see citing works
Xie, S., Yue, C., Ye, S., & Li, Z. (2024) · Physical Chemistry Chemical Physics · doi:10.1039/d3cp05957j · Cited by 4 · see citing works
Li, N., Xu, J., Li, Y., Elango, J., & Wu, W. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051869 · Cited by 4 · see citing works
Protamine-Based Nanotherapeutics for Gene Delivery to Glioblastoma Cells
Barrios-Esteban, S., Reimóndez-Troitiño, S., Cabezas‐Sainz, P., de la Fuente, M., Sanchez, L. E., Rahman, R., Alexander, C., García-Fuentes, M., & Csaba, N. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.4c01269 · Cited by 4 · see citing works
Gelatin and lipidoid integrate to create gelasomes to enhance siRNA delivery with low toxicity
Gangula, A., Suresh, D., Babu, A. S., Li, Z., Upendran, A., & Kannan, R. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.06.008 · Cited by 3 · see citing works
Protamine nanocapsules as gene delivery carriers for the treatment of intraocular tumors
Barrios-Esteban, S., Alcalde, I., Chacón, M., Merayo‐Lloves, J., de la Fuente, M., & Csaba, N. (2025) · Drug Delivery and Translational Research · doi:10.1007/s13346-025-01849-1 · Cited by 3 · see citing works
Targeted gene delivery through receptors with lipid nanoparticles
Muripiti, V., Velidandia, A., Sharma, Y., Gondru, R., Arya, C. G., & Banothu, J. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.105457 · Cited by 3 · see citing works
Wu, J., Tan, T., Chen, J., & Zhang, Y. (2025) · Biomacromolecules · doi:10.1021/acs.biomac.4c01572 · Cited by 2 · see citing works
Tissue‐specific gene delivery approaches
Nasr, S. S., Cheema, Y., Stern, A., Tabah, O., Poore, S., & Duncan, G. A. (2026) · Bioengineering & Translational Medicine · doi:10.1002/btm2.70125 · Cited by 3 · see citing works
Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy
Holzinger, T., Frei, J., Jarzębska, N. T., Beer, H., Kündig, T. M., Pascolo, S., Läuchli, S., & Mellett, M. (2024) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000001644 · Cited by 2 · see citing works
Self-citationmRNA vaccine delivery strategies for cancer therapy
Zhang, H., Zhang, H., Xu, B., & Liu, H. (2024) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/tb-2024-0670 · Cited by 2 · see citing works
Pan, M., Cao, W., Zhai, J., Zheng, C., Xu, Y., & Zhang, P. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.143134 · Cited by 2 · see citing works
Dissanayake, R. K., Mishra, V. K., & Ahmed, M. (2025) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2025.103697 · Cited by 2 · see citing works
Engineering a Novel Modular Adenoviral mRNA Delivery Platform Based on Tag/Catcher Bioconjugation
Geng, K., Rice-Boucher, P. J., Kashentseva, E. A., Dmitriev, I. P., Lu, Z. H., Goedegebuure, S. P., Gillanders, W. E., & Curiel, D. T. (2023) · Viruses · doi:10.3390/v15112277 · Cited by 3 · see citing works
Saha, S., Chakraborty, S., & Nayak, A. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105345 · Cited by 1 · see citing works
Dodopoulos, A., Syrianou, N., & Stamatopoulos, P. (2026) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2026.108445 · Cited by 1 · see citing works
RNA with chemotherapeutic base analogues as a dual-functional anti-cancer drug
Jarzębska, N. T., Tusup, M., Frei, J., Weiß, T., Holzinger, T., Mellett, M., Diken, M., Bredl, S., Weller, M., Speck, R. F., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2147665 · Cited by 1 · see citing works
Self-citationAdditional Gene Therapeutic Platforms
Langel, Ü. (2023) · Springer eBooks · doi:10.1007/978-3-031-38731-9_6 · Cited by 1 · see citing works
Langel, Ü. (2023) · Springer eBooks · doi:10.1007/978-3-031-38731-9_16 · Cited by 1 · see citing works
Jiang, Q., Su, K., Li, G., Luo, H., Wang, H., Luo, J., Zhong, Y.-N., Li, Q., Zhang, Z., Zhang, H., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.13.688269 · Cited by 1 · see citing works
Faust, A., Bäumer, N., Schlütermann, A., Becht, M., Greune, L., Geyer, C., Rüter, C., Margeta, R., Wittmann, L., Dersch, P., et al. (2021) · Angewandte Chemie · doi:10.1002/ange.202109769
Fu, N., Li, J., Wu, J., Gao, W., Zhang, X., & Shen, B. (2022) · Dyes and Pigments · doi:10.1016/j.dyepig.2022.110340
Xie, S., Yue, C., Ye, S., & Li, Z. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.14.528413
Environment‐Responsive Peptide Dimers Bind and Stabilize Double‐Stranded RNA
McLoughlin, N. M., Albers, M. A., Camps, E. C., Paulus, J., Ran, Y. A., Neubacher, S., Hennig, S., Brock, R. E., & Grossmann, T. N. (2023) · Angewandte Chemie · doi:10.1002/ange.202308028
mRNA vaccines: a promising solution for incurable diseases
Ge, H., Hei, Y., & Wu, J. (2024) · International Conference on Biological Engineering and Medical Science (ICBioMed) · doi:10.1117/12.3021657
From Sea to Cell: Marine Peptides as Key Players in siRNA-Mediated Cancer Therapy
Alfaray, R. I., Amalia, N., Ali, M., Supranoto, Y. T. N., Darmawan, H. E., Purnomo, A. F., Pramono, A., Taslim, N. A., Tjandrawinata, R. R., Tallei, T. E., et al. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_490
Puri, D., Bott, A., Baranda, M. V., Torlak, E. D., Merges, G. E., Schorle, H., & Wagner, W. (2025) · Epigenetics & Chromatin · doi:10.1186/s13072-025-00633-2
mRNA-Based Biosimilars as Next-Generation Vaccines
Upadhyay, A., & Rani, V. (2025) · Advances in Science, Technology & Innovation/Advances in science, technology & innovation · doi:10.1007/978-3-031-80973-6_1
The Utility and Challenges of Liquid Biopsy
Kikuchi, A., Naruse, A., NONAKA, K., MORI, M., & Tsutsumiuchi, K. (2025) · Thermal Medicine · doi:10.3191/thermalmed.41.57
Improved Messenger RNA Stability and Biocompatibility Through Self‐Gelatinizable Nucleic Acids
Tanifuji, T., Kusamori, K., Tanaka, C., Sakai, H., Itakura, S., & Nishikawa, M. (2026) · Biotechnology and Bioengineering · doi:10.1002/bit.70158
An overview of the mRNA applications and their therapeutic functions in clinical development
Ramakrishnaiah, T. N., Srikar, K. S., Deb, A., Ahmed, K. S., Chandraghatgi, R. R., Sarin, Y., Roopini, K., & Rajashekara, S. (2026) · Next research. · doi:10.1016/j.nexres.2026.101413
Liao, X., Han, D., Qi, L., Huang, Q., Gao, Q., He, X., Guo, T., Lei, J.-J., & Cheng, S. (2026) · Small · doi:10.1002/smll.202514860
Self-Assembling Short Peptide Carriers for Gene Delivery
An, L., Xu, Z., & Zhang, X. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27083464
Tracking the Trail of Monkeypox: From Origins to Outbreak Control
Jangir, A., Swami, A., Kumari, N. P., Kumar, H., Arya, H., Yadav, N., Kumar, D., & Bhatt, T. K. (2026) · Cell Biochemistry and Function · doi:10.1002/cbf.70239
Gao, Q.-Y., Han, D., Liao, X., Lei, J.-J., Qi, L., Huang, Q.-Y., Fu, F.-F., & Cheng, S. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.153260
Yazdani, S., Pazuki, G., Mozaffarian, M., & Hadidi, N. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-33639-3.00006-4
Liao, X., Han, D., Gao, Q., Huang, Q.-Y., Qi, L., Fu, F.-F., Yang, C. Y., Jiang, Z.-M., Lei, J.-J., & Cheng, S. (2026) · Small · doi:10.1002/smll.74776
Nonviral nucleic acid delivery systems: specific features of polymeric carriers
Shaputkin, E., Nifant'ev, I., & Ivchenko, P. (2026) · Russian Chemical Reviews · doi:10.59761/rcr5222
Karim, M. E., Holl, M. M. B., Corrie, S. R., & Chowdhury, E. H. (2026) · Cancer Gene Therapy · doi:10.1038/s41417-026-01085-w
- Authors
- Jarzebska, N. T., Mellett, M., Frei, J., Kündig, T. M., & Pascolo, S.
- Affiliations
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091 Zürich, Switzerland
- University of Zurich (CH)
- Corresponding author
- Pascolo, Steve
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2021-06-14
- Volume
- 13
- Issue
- 6
- Pages
- 877
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC8231816
- OpenAlex
- W3167965536
- Cited by
- 95
- References
- 75
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 17 · 2023: 23 · 2022: 11 · 2021: 5
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- Preprints.org (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Universität Zürich
- Foundation for Research in Science and the Humanities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- protamine, RNA transfection, RNA delivery, RNA stabilization, RNA vaccines, cationic peptides, cell-penetrating peptides, immunostimulatory properties, nucleic acid stability, heparin neutralization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
