Objectives

chemicallytech

Fine Chemical Technologies

Тонкие химические технологии

2410-65932686-7575

MIREA – Russian Technological University (RTU MIREA).

10.32362/2410-6593-2026-21-1-51-72

WYDPLI

chemicallytech-2351

Research Article

CHEMISTRY AND TECHNOLOGY OF MEDICINAL COMPOUNDS AND BIOLOGICALLY ACTIVE SUBSTANCES

ХИМИЯ И ТЕХНОЛОГИЯ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ И БИОЛОГИЧЕСКИ АКТИВНЫХ СОЕДИНЕНИЙ

Ionizable lipids as a promising platform for creating mRNA vaccines

Ионизируемые липиды как перспективная платформа для создания мРНК-вакцин

https://orcid.org/0009-0004-2644-6921

Милагина

С. В.

Milagina

Svetlana V.

Милагина Светлана Викторовна, магистрант, инженер, кафедра химии и технологии биологически активных соединений, медицинской и органической химии им. Н.А. Преображенского,

119454, Россия, Москва, пр-т Вернадского, д. 78.

Svetlana V. Milagina, Master Student, Engineer, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry,

78, Vernadskogo pr., Moscow, 119454.

milagina.s.v@yandex.ru

https://orcid.org/0000-0001-6591-950X

Пучков

П. А.

Puchkov

Pavel A.

Пучков Павел Анатольевич, к.х.н., доцент, кафедра химии и технологии биологически активных соединений, медицинской и органической химии им. Н.А. Преображенского,

119454, Россия, Москва, пр-т Вернадского, д. 86.

Scopus Author ID: 55900634000.

Pavel A. Puchkov, Cand. Sci. (Chem.), Associate Professor, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry,

78, Vernadskogo pr., Moscow, 119454,

Scopus Author ID: 55900634000.

puchkov_pa@mail.ru

МИРЭА – Российский технологический университет (Институт тонких химических технологий им. М.В. ЛомоносоваРоссияMIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)Russian Federation

2026

05032026

2115172

2026

Милагина С.В., Пучков П.А.

Milagina S.V., Puchkov P.A.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.finechem-mirea.ru/jour/article/view/2351

Objectives

Objectives. Gene therapy involves the administration of various types of therapeutic nucleic acids into the organism, in order to treat severe hereditary diseases, as well as cancer. Furthermore, the COVID-19 pandemic demonstrated the possibility of rapid development and the effectiveness of both DNA and mRNA vaccines for the prevention of viral diseases. Numerous studies in the field of gene therapy have revealed that in most cases successful delivery of nucleic acids requires a special delivery system which protects nucleic acids from the effects of external and internal biological factors. Among the various types of such tools, non-viral delivery systems have proven to be the most versatile and safe ones. In the case of mRNA delivery, such systems are usually called mRNA vaccines, consisting of cationic or ionizable lipids. The purpose of this review is to justify the choice of the optimal structure of lipid components of mRNA vaccines and highlight the current prospects for their clinical use.

Results

Results. In this review, we have considered the evolution of lipid structures, from cationic to ionizable, as the main components of mRNA delivery systems. Furthermore, the study demonstrated the necessity to use other types of lipids in mRNA vaccines. It also presents a review of clinical trials of mRNA vaccines against viral and oncological diseases, and provides recommendations for the design of the optimal structure of both cationic and ionizable lipids.

Conclusions

Conclusions. The most promising lipids for the development of mRNA vaccines are ionizable. They do not have a permanent positive charge which reduces their cytotoxicity and undesirable binding to components of the immune system. In general, mRNA vaccines can be universal and effective means for treating various types of diseases. However, their composition needs to be careful optimized.

Цели

Цели. Генная терапия подразумевает введение в организм различных типов терапевтических нуклеиновых кислот для лечения тяжелых наследственных, а также онкологических заболеваний. Кроме того, пандемия COVID-19 показала возможность быстрой разработки и эффективность использования ДНК- и мРНК-вакцин для профилактики вирусных заболеваний. Многочисленные исследования в области генной терапии выявили, что в большинстве случаев успешная доставка нуклеиновых кислот требует наличия специальной системы доставки, защищающей нуклеиновые кислоты от действия внешних и внутренних биологических факторов. Среди различных типов таких инструментов наиболее универсальными и безопасными зарекомендовали себя невирусные системы доставки, такие как катионные липосомы и липидные наночастицы, формируемые из катионных или ионизируемых липидов соответственно. В случае доставки мРНК такие системы обычно называют мРНК-вакцинами. Целью данного обзора являлось обоснование выбора оптимальной структуры липидных компонентов мРНК-вакцин и освещение текущих перспектив их клинического применения.

Результаты

Результаты. В данном обзоре мы рассмотрели эволюцию структур липидов, начиная с катионных и заканчивая ионизируемыми, как основных компонентов систем доставки мРНК. Кроме того, показана необходимость использования в составе мРНК-вакцин других типов липидов, проведен обзор клинических испытаний мРНК-вакцин против вирусных и онкологических заболеваний, даны рекомендации по дизайну оптимальной структуры катионных и ионизируемых липидов.

Выводы

Выводы. Наиболее перспективными липидами для разработки мРНК-вакцин являются ионизируемые. Они не обладают постоянным положительным зарядом, что снижает их цитотоксичность и нежелательное связывание с компонентами иммунной системы. В целом, мРНК-вакцины могут стать универсальным и эффективным средством лечения различных типов заболеваний, но требуют тщательной оптимизации их состава.

генная терапиямРНК-вакциныкатионные липосомылипидные наночастицыкатионные липидыионизируемые липиды

gene therapymRNA vaccinescationic liposomeslipid nanoparticlescationic lipidsionizable lipids

Исследование выполнено при финансовой поддержке Российского научного фонда в рамках научных проектов 23-73-10168 (раздел «Эволюция липидных структур») и 22-75-10153 (раздел «Клинические испытания мРНК-вакцин»). Авторы выражают благодарность Е.В. Шмендель (Институт тонких химических технологий им. М.В. Ломоносова, МИРЭА – Российский технологический университет) за ценные замечания при подготовке рукописи.

The study was supported by the Russian Science Foundation (grant No. 23-73-10168 for the section “Lipid structure evolution”; grant No. 22-75-10153 for the section “Clinical trials of mRNA vaccines”). The authors gratefully acknowledge E.V. Shmendel (M.V. Lomonosov Institute of Fine Chemical Technologies, MIREA – Russian Technological University) for the valuable critical comments on the manuscript.

References1

Puumalainen A.M., Vapalahti M., Agrawal R.S., Kossila M., Laukkanen J., Lehtolainen P., Viita H., Paljärvi L., Vanninen R., Ylä-Herttuala S. β-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Human Gene Ther. 1998;9(12):1769–1774. https://doi.org/10.1089/hum.1998.9.12-1769

Blaese R.M., Culver K.W., Miller A.D., Carter C.S., Fleisher T., Clerici M., Shearer G., Chang L., Chiang Y., Tolstoshev P., Greenblatt J.J, Rosenberg S.A., Klein H., Berger M., Mullen C.A., Ramsey W.J., Muul L., Morgan R.A., Anderson W.F. T Lymphocyte-Directed Gene Therapy for ADA−SCID: Initial Trial Results After 4 Years. Science. 1995;270(5235):475–480. https://doi.org/10.1126/science.270.5235.475

Kulkarni J.A., Witzigmann D., Thomson S.B., Chen S., Leavitt B.R., Cullis P.R., van der Meel R. The current landscape of nucleic acid therapeutics. Nature Nanotechnol. 2021;16: 630–643. https://doi.org/10.1038/s41565-021-00898-0

Liu G., Lin Q., Jin S., Gao C. The CRISPR-Cas toolbox and gene editing technologies. Mol. Cell. 2022;82(2):333–347. https://doi.org/10.1016/J.MOLCEL.2021.12.002

Liu C., Zhang L., Zhu W., Guo R., Sun H., Chen X., Deng N. Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy. Mol. Ther. Methods Clin. Dev. 2020;18: 751–764. https://doi.org/10.1016/j.omtm.2020.07.015

Goradel N.H., Negahdari B., Ghorghanlu S., Jahangiri S., Arashkia A. Strategies for enhancing intratumoral spread of oncolytic adenoviruses. Pharmacol. Ther. 2020;213:107586. https://doi.org/10.1016/j.pharmthera.2020.107586

Володин Т.А., Поликашина П.П., Буданова У.А., Себякин Ю.Л. Симметричные и асимметричные димерные катионные амфифилы на основе липопептидов нерегулярного строения в качестве потенциальных компонентов катионных липосом. Тонкие химические технологии. 2025;20(5):441–453. https://doi.org/10.32362/2410-6593-2025-20-5-441-453

Volodin T.A., Polikashina P.P., Budanova U.A., Sebyakin Y.L. Symmetrical and asymmetric dimeric cationic amphiphiles based on lipopeptides of irregular structure as potential components of cationic liposomes. Fine Chem. Technol. 2025;20(5):441–453. https://doi.org/10.32362/2410-6593-2025-20-5-441-453

Wang C., Pan C., Yong H., Wang F., Bo T., Zhao Y., Ma B., He W., Li M. Emerging non-viral vectors for gene delivery. J. Nanobio- technology. 2023;21:272. https://doi.org/10.1186/s12951-023-02044-5

Law S.S.Y., Liou G., Nagai Y., Giménez-Dejoz J., Tateishi A., Tsuchiya K., Kodama Y., Fujigaya T., Numata K. Polymercoated carbon nanotube hybrids with functional peptides for gene delivery into plant mitochondria. Nature Communications. 2022;13:2417. https://doi.org/10.1038/s41467-022-30185-y

Lin G., Revia R.A., Zhang M. Inorganic Nanomaterial-Mediated Gene Therapy in Combination with Other Antitumor Treatment Modalities. Adv. Funct. Mater. 2021;31(5):2007096. https://doi.org/10.1002/adfm.202007096

Lin G., Revia R.A., Zhang M. Inorganic NanomaterialMediated Gene Therapy in Combination with Other Antitumor Treatment Modalities. Adv. Funct. Mater. 2021;31(5):2007096. https://doi.org/10.1002/adfm.202007096

Jones I., Roy P. Sputnik V COVID-19 vaccine candidate appears safe and effective. The Lancet. 2021;397(10275): 642–643. https://doi.org/10.1016/S0140-6736(21)00191-4

Walsh E.E., Frenck R.W., Falsey A.R., Kitchin N., Absalon J., Gurtman A., Lockhart S., Neuzil K., Mulligan M.J., Bailey R., Swanson K.A., Li P., Koury K., Kalina W., Cooper D., Fontes-Garfias C., Shi P.-Y., Türeci Ö., Tompkins K.R., Lyke K.E., Raabe V., Dormitzer P.R., Jansen K.U., Şahin U., Gruber W.C. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. New Engl. J. Med. 2020;383(25): 2439–2450. https://doi.org/10.1056/nejmoa2027906

Baden L.R., El Sahly H.M., Essink B., Kotloff K., Frey S., Novak R., Diemert D., Spector S.A., Rouphael N., Creech C.B., McGettigan J., Khetan S., Segall N., Solis J., Brosz A., Fierro C., Schwartz H., Neuzil K., Corey L., Gilbert P., Janes H., Follmann D., Marovich M., Mascola J., Polakowski L., Ledgerwood J., Graham B.S., Bennett H., Pajon R., Knightly C., Leav B., Deng W., Zhou H., Han S., Ivarsson M., Miller J., Zaks T. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New Engl. J. Med. 2021;384(5):403–416. https://doi.org/10.1056/nejmoa2035389

Jin L., Zeng X., Liu M., Deng Y., He N. Current progress in gene delivery technology based on chemical methods and nano-carriers. Theranostics. 2014;4(3):240–255. https://doi.org/10.7150/thno.6914

Kranz L.M., Diken M., Haas H., Kreiter S., Loquai C., Reuter K.C., Meng M., Fritz D., Vascotto F., Hefesha H., Grunwitz C., Vormehr M., Hüsemann Y., Selmi A., Kuhn A.N., Buck J., Derhovanessian E., Rae R., Attig S., Diekmann J., Jabulowsky R.A., Heesch S., Hassel J., Langguth P., Grabbe S., Huber C., Türeci Ö., Sahin U. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396–401. https://doi.org/10.1038/nature18300

Sayour E.J., Grippin A., De Leon G., Stover B., Rahman M., Karachi A., Wummer B., Moore G., Castillo-Caro P., Fredenburg K., Sarkisian M.R., Huang J., Deleyrolle L.P., Sahay B., Carrera-Justiz S., Mendez-Gomez H.R., Mitchell D.A. Personalized Tumor RNA Loaded Lipid-Nanoparticles Prime the Systemic and Intratumoral Milieu for Response to Cancer Immunotherapy. Nano Lett. 2018;18(10):6195–6206. https://doi.org/10.1021/acs.nanolett.8b02179

Melo M., Porter E., Zhang Y., Silva M., Li N., Dobosh B., Liguori A., Skog P., Landais E., Menis S., Sok D., Nemazee D., Schief W.R., Weiss R., Irvine D.J. Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles. Mol. Therapy. 2019;27(12): 2080–2090. https://doi.org/10.1016/j.ymthe.2019.08.007

Melo M., Porter E., Zhang Y., Silva M., Li N., Dobosh B., Liguori A., Skog P., Landais E., Menis S., Sok D., Nemazee D., Schief W.R., Weiss R., Irvine D.J. Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for SelfAssembly into Nanoparticles. Mol. Therapy. 2019;27(12): 2080–2090. https://doi.org/10.1016/j.ymthe.2019.08.007

Krienke C., Kolb L., Diken E., Streuber M., Kirchhoff S., Bukur T., Akilli-Öztürk Ö., Kranz L.M., Berger H., Petschenka J., Diken M., Kreiter S., Yogev N., Waisman A., Karikó K., Türeci Ö., Sahin U. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021;371(6525):145–153. https://doi.org/10.1126/science.aay3638

Bevers S., Kooijmans S.A.A., Van de Velde E., Evers M.J.W., Seghers S., Gitz-Francois J.J.J.M., van Kronenburg N.C.H., Fens M.H.A.M., Mastrobattista E., Hassler L., Sork H., Lehto T., Ahmed K.E., El Andaloussi S., Fiedler K., Breckpot K., Maes M., Van Hoorick D., Bastogne T., Schiffelers R.M., De Koker S. mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells. Mol. Therapy. 2022;30(9):3078–3094. https://doi.org/10.1016/j.ymthe.2022.07.007

Anderluzzi G., Lou G., Gallorini S., Brazzoli M., Johnson R., O’Hagan D.T., Baudner B.C., Perrie Y. Investigating the impact of delivery system design on the efficacy of selfamplifying RNA vaccines. Vaccines (Basel). 2020;8:212. https://doi.org/10.3390/vaccines8020212

Fedorovskiy A.G., Antropov D.N., Dome A.S., Puchkov P.A., Makarova D.M., Konopleva M.V., Matveeva A.M., Panova E.A., Shmendel E.V., Maslov M.A., Dmitriev S.E., Stepanov G.A., Markov O.V. Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues. Pharmaceutics. 2024;16(5):684. https://doi.org/10.3390/pharmaceutics16050684

Cullis P.R., Hope M.J. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol. Therapy. 2017;25(7): 1467–1475. https://doi.org/10.1016/j.ymthe.2017.03.013

Farbiak L., Cheng Q., Wei T., Álvarez-Benedicto E., Johnson L.T., Lee S., Siegwart D.J. All-In-One Dendrimer-Based Lipid Nanoparticles Enable Precise HDR-Mediated Gene Editing In Vivo. Adv. Mater. 2021;33(30):e2006619. https://doi.org/10.1002/adma.202006619

Farbiak L., Cheng Q., Wei T., Álvarez-Benedicto E., Johnson L.T., Lee S., Siegwart D.J. All-In-One DendrimerBased Lipid Nanoparticles Enable Precise HDR-Mediated Gene Editing In Vivo. Adv. Mater. 2021;33(30):e2006619. https://doi.org/10.1002/adma.202006619

Heyes J., Palmer L., Bremner K., MacLachlan I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Controll. Release. 2005;107(2):276–287. https://doi.org/10.1016/j.jconrel.2005.06.014

Sato Y., Hashiba K., Sasaki K., Maeki M., Tokeshi M., Harashima H. Understanding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo. J. Controll. Release. 2019;295:140–152. https://doi.org/10.1016/j.jconrel.2019.01.001

Patel S., Ryals R.C., Weller K.K., Pennesi M.E., Sahay G. Lipid nanoparticles for delivery of messenger RNA to the back of the eye. J. Controll. Release. 2019;303:91–100. https://doi.org/10.1016/J.JCONREL.2019.04.015

Gote V., Bolla P.K., Kommineni N., Butreddy A., Nukala P.K., Palakurthi S.S., Khan W. A Comprehensive Review of mRNA Vaccines. Int. J. Mol. Sci. 2023;24:2700. https://doi.org/10.3390/ijms24032700

Semple S.C., Akinc A., Chen J., Sandhu A.P., Mui B.L., Cho C.K., Sah DW.Y., Stebbing D., Crosley E.J., Yaworski E., Hafez I.M., Dorkin J.R., Qin J., Lam K., Rajeev K.G., Wong K.F., Jeffs L.B., Nechev L., Eisenhardt M.L., Jayaraman M., Kazem M., Maier M.A., Srinivasulu M., Weinstein M.J., Chen Q., Alvarez R., Barros S.A., De S., Klimuk S.K., Borland T., Kosovrasti V., Cantley W.L., Tam Y.K., Manoharan M., Ciufolini M.A., Tracy M.A., De Fougerolles A., MacLachlan I., Cullis P.R., Madden T.D., Hope M.J. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 2010;28:172–176. https://doi.org/10.1038/nbt.1602

McKay P.F., Hu K., Blakney A.K., Samnuan K., Brown J.C., Penn R., Zhou J., Bouton C.R., Rogers P., Polra K., Lin P.J.C., Barbosa C., Tam Y.K., Barclay W.S., Shattock R.J. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat. Commun. 2020;11:3523. https://doi.org/10.1038/S41467-020-17409-9

Akinc A., Maier M.A., Manoharan M., Fitzgerald K., Jayaraman M., Barros S., Ansell S., Du X., Hope M.J., Madden T.D., Mui B.L., Semple S.C., Tam Y.K., Ciufolini M., Witzigmann D., Kulkarni J.A., van der Meel R., Cullis P.R. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 2019;14:1084–1087. https://doi.org/10.1038/s41565-019-0591-y

Zhang M., Sun J., Li M., Jin X. Modified mRNA-LNP Vaccines Confer Protection against Experimental DENV-2 Infection in Mice. Mol. Ther. Methods Clin. Dev. 2020;18:702–712. https://doi.org/10.1016/j.omtm.2020.07.013

Sabnis S., Kumarasinghe E.S., Salerno T., Mihai C., Ketova T., Senn J.J., Lynn A., Bulychev A., McFadyen I., Chan J., Almarsson Ö., Stanton M.G., Benenato K.E. A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates. Mol. Therapy. 2018;26(6):1509–1519. https://doi.org/10.1016/j.ymthe.2018.03.010

Huo H., Cheng X., Xu J., Lin J., Chen N., Lu X. A fluorinated ionizable lipid improves the mRNA delivery efficiency of lipid nanoparticles. J. Mater. Chem. B. 2023;11(19):4171–4180. https://doi.org/10.1039/d3tb00516j

Corbett K.S., Edwards D.K., Leist S.R., Abiona O.M., Boyoglu-Barnum S., Gillespie R.A., Himansu S., Schäfer A., Ziwawo C.T., DiPiazza A.T., Dinnon K.H., Elbashir S.M., Shaw C.A., Woods A., Fritch E.J., Martinez D.R., Bock K.W., Minai M., Nagata B.M., Hutchinson G.B., Wu K., Henry C., Bahl K., Garcia-Dominguez D., Ma L.Z., Renzi I., Kong W.P., Schmidt S.D., Wang L., Zhang Y., Phung E., Chang L.A., Loomis R.J., Altaras N.E., Narayanan E., Metkar M., Presnyak V., Liu C., Louder M.K., Shi W., Leung K., Yang E.S., West A., Gully K.L., Stevens L.J., Wang N., Wrapp D., Doria-Rose N.A., Stewart-Jones G., Bennett H., Alvarado G.S., Nason M.C., Ruckwardt T.J., McLellan J.S., Denison M., Chappell J.D., Moore I.N., Morabito K.M., Mascola J.R., Baric R.S., Carfi A., Graham B.S. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020;586:567–571. https://doi.org/10.1038/s41586-020-2622-0

Tanaka H., Sakurai Y., Anindita J., Akita H. Development of lipid-like materials for RNA delivery based on intracellular environment-responsive membrane destabilization and spontaneous collapse. Adv. Drug. Deliv. Rev. 2020; 154-155:210–226. https://doi.org/10.1016/j.addr.2020.07.001

Buschmann M.D., Carrasco M.J., Alishetty S., Paige M., Alameh M.G., Weissman D. Nanomaterial delivery systems for mRNA vaccines. Vaccines (Basel). 2021;9(1):65. https://doi.org/10.3390/vaccines9010065

Hassett K.J., Higgins J., Woods A., Levy B., Xia Y., Hsiao C.J., Acosta E., Almarsson Ö., Moore M.J., Brito L.A. Impact of lipid nanoparticle size on mRNA vaccine immunogenicity. J. Controll. Release. 2021;335:237–246. https://doi.org/10.1016/j.jconrel.2021.05.021

Vogel A.B., Kanevsky I., Che Y., Swanson K.A., Muik A., Vormehr M., Kranz L.M., Walzer K.C., Hein S., Güler A., Loschko J., Maddur M.S., Ota-Setlik A., Tompkins K., Cole J., Lui B.G., Ziegenhals T., Plaschke A., Eisel D., Dany S.C., Fesser S., Erbar S., Bates F., Schneider D., Jesionek B., Sänger B., Wallisch A.K., Feuchter Y., Junginger H., Krumm S.A., Heinen A.P., Adams-Quack P., Schlereth J., Schille S., Kröner C., de la Caridad Güimil Garcia R., Hiller T., Fischer L., Sellers R.S., Choudhary S., Gonzalez O., Vascotto F., Gutman M.R., Fontenot J.A., Hall-Ursone S., Brasky K., Griffor M.C., Han S., Su A.A.H., Lees J.A., Nedoma N.L., Mashalidis E.H., Sahasrabudhe P.V., Tan C.Y., Pavliakova D., Singh G., Fontes-Garfias C., Pride M., Scully I.L., Ciolino T., Obregon J., Gazi M., Carrion R., Alfson K.J., Kalina W.V., Kaushal D., Shi P.Y., Klamp T., Rosenbaum C., Kuhn A.N., Türeci Ö., Dormitzer P.R., Jansen K.U., Sahin U. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature. 2021;592:283–289. https://doi.org/10.1038/s41586-021-03275-y

Panova E.A., Kleymenov D.A., Shcheblyakov D.V., Bykonia E.N., Mazunina E.P., Dzharullaeva A.S., Zolotar A.N., Derkaev A.A., Esmagambetov I.B., Sorokin I.I., Usachev E.V., Noskov A.N., Ivanov I.A., Zatsepin T.S., Dmitriev S.E., Gushchin V.A., Naroditsky B.S., Logunov D.Y., Gintsburg A.L. Single-domain antibody delivery using an mRNA platform protects against lethal doses of botulinum neurotoxin A. Front. Immunol. 2023;14:1098302. https://doi.org/10.3389/fimmu.2023.1098302

Mazunina E.P., Gushchin V.A., Bykonia E.N., Kleymenov D.A., Siniavin A.E., Kozlova S.R., Mukasheva E.A., Shidlovskaya E.V., Kuznetsova N.A., Usachev E.V., Zlobin V.I., Burtseva E.I., Ivanov R.A., Logunov D.Y., Gintsburg A.L. Immunogenicity and Efficacy of Combined mRNA Vaccine Against Influenza and SARS-CoV-2 in Mice Animal Models. Vaccines. 2024;12(11): 1206. https://doi.org/10.3390/VACCINES12111206

Mazunina E.P., Gushchin V.A., Kleymenov D.A., Siniavin A.E., Burtseva E.I., Shmarov M.M., Mukasheva E.A., Bykonia E.N., Kozlova S.R, Evgrafova E.A., Zolotar A.N., Shidlovskaya E.V., Kirillova E.S., Krepkaia A.S., Usachev E.V., Kuznetsova N.A., Ivanov I.A., Dmitriev S.E., Ivanov R.A., Logunov D.Y., Gintsburg A.L. Trivalent mRNA vaccine-candidate against seasonal flu with cross-specific humoral immune response. Front. Immunol. 2024;15:1381508. https://doi.org/10.3389/fimmu.2024.1381508

Miao L., Lin J., Huang Y., Li L., Delcassian D., Ge Y., Shi Y., Anderson D.G. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 2020;11:2424. https://doi.org/10.1038/s41467-020-16248-y

Miao L., Zhang Y., Huang L. mRNA vaccine for cancer immunotherapy. Mol. Cancer. 2021;20:41. https://doi.org/10.1186/s12943-021-01335-5

Lokugamage M.P., Vanover D., Beyersdorf J., Hatit M.Z.C., Rotolo L., Echeverri E.S., Peck HE., Ni H., Yoon J.K., Kim Y.T., Santangelo P.J., Dahlman J.E. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng. 2021;5:1059–1068. https://doi.org/10.1038/s41551-021-00786-x

Ogata F.T., Branco V., Vale F.F., Coppo L. Glutaredoxin: Discovery, redox defense and much more. Redox Biol. 2021;43: 101975. https://doi.org/10.1016/J.REDOX.2021.101975

Begas P., Liedgens L., Moseler A., Meyer A.J., Deponte M. Glutaredoxin catalysis requires two distinct glutathione interaction sites. Nat. Commun. 2017;8:14835. https://doi.org/10.1038/ncomms14835

Gallogly M.M., Starke D.W., Mieyal J.J. Mechanistic and kinetic details of catalysis of thiol-disulfide exchange by glutaredoxins and potential mechanisms of regulation. Antioxid Redox Signal. 2009;11(5):1059–1081. https://doi.org/10.1089/ars.2008.2291

Holmgren A. Thioredoxin. Annu. Rev. Biochem. 1985;54: 237–271. https://doi.org/10.1146/annurev.bi.54.070185.001321

Powis G., Montfort W.R. Properties and biological activities of thioredoxins. Annu. Rev. Pharmacol. Toxicol. 2001;41: 261–295. https://doi.org/10.1146/annurev.pharmtox.41.1.261

Luster A.D., Weinshank R.L., Feinman R., Ravetch J.V. Molecular and biochemical characterization of a novel gamma-interferoninducible protein. J. Biol. Chem. 1988;263(24):12036–12043. https://doi.org/10.1016/S0021-9258(18)37889-X

Arunachalam B., Phan U.T., Geuze H.J., Cresswell P. Enzymatic reduction of disulfide bonds in lysosomes: Characterization of a Gamma-interferon-inducible lysosomal thiol reductase (GILT). Proc. Natl. Acad. Sci. USA. 2000;97(2):745–750. https://doi.org/10.1073/pnas.97.2.745

Shirazi R.S., Ewert K.K., Leal C., Majzoub R.N., Bouxsein N.F., Safinya C.R. Synthesis and characterization of degradable multivalent cationic lipids with disulfide-bond spacers for gene delivery. Biochim. Biophys. Acta Biomembr. 2011;1808(9): 2156–2166. https://doi.org/10.1016/j.bbamem.2011.04.020

Tanaka H., Takahashi T., Konishi M., Takata N., Gomi M., Shirane D., Miyama R., Hagiwara S., Yamasaki Y., Sakurai Y., Ueda K., Higashi K., Moribe K., Shinsho E., Nishida R., Fukuzawa K., Yonemochi E., Okuwaki K., Mochizuki Y., Nakai Y., Tange K., Yoshioka H., Tamagawa S., Akita H. Self-Degradable Lipid-Like Materials Based on “Hydrolysis accelerated by the intra-Particle Enrichment of Reactant (HyPER)” for Messenger RNA Delivery. Adv. Funct. Mater. 2020;30(34):1910575. https://doi.org/10.1002/adfm.201910575

Tanaka H., Takahashi T., Konishi M., Takata N., Gomi M., Shirane D., Miyama R., Hagiwara S., Yamasaki Y., Sakurai Y., Ueda K., Higashi K., Moribe K., Shinsho E., Nishida R., Fukuzawa K., Yonemochi E., Okuwaki K., Mochizuki Y., Nakai Y., Tange K., Yoshioka H., Tamagawa S., Akita H. Self-Degradable Lipid-Like Materials Based on “Hydrolysis accelerated by the intraParticle Enrichment of Reactant (HyPER)” for Messenger RNA Delivery. Adv. Funct. Mater. 2020;30(34):1910575. https://doi.org/10.1002/adfm.201910575

Akita H., Ishiba R., Togashi R., Tange K., Nakai Y., Hatakeyama H., Harashima H. A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma. J. Controll. Release. 2015;200:97–105. https://doi.org/10.1016/j.jconrel.2014.12.029

Miyabe H., Hyodo M., Nakamura T., Sato Y., Hayakawa Y., Harashima H. A new adjuvant delivery system “cyclic di-GMP/YSK05 liposome” for cancer immunotherapy. J. Controll. Release. 2014;184:20–27. https://doi.org/10.1016/j.jconrel.2014.04.004

Shobaki N., Sato Y., Harashima H. Mixing lipids to manipulate the ionization status of lipid nanoparticles for specific tissue targeting. Int. J. Nanomedicine. 2018;13:8395–8410. https://doi.org/10.2147/IJN.S188016

Warashina S., Nakamura T., Sato Y., Fujiwara Y., Hyodo M., Hatakeyama H., Harashima H. A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells. J. Controll. Release. 2016;225:183–191. https://doi.org/10.1016/j.jconrel.2016.01.042

Shobaki N., Sato Y., Suzuki Y., Okabe N., Harashima H. Manipulating the function of tumor-associated macrophages by siRNA-loaded lipid nanoparticles for cancer immunotherapy. J. Controll. Release. 2020;325:235–248. https://doi.org/10.1016/j.jconrel.2020.07.001

Hashiba K., Taguchi M., Sakamoto S., Otsu A., Maeda Y., Ebe H., Okazaki A., Harashima H., Sato Y. Overcoming thermostability challenges in mRNA–lipid nanoparticle systems with piperidinebased ionizable lipids. Commun. Biol. 2024;7:556. https://doi.org/10.1038/s42003-024-06235-0

Akinc A., Goldberg M., Qin J., Dorkin J.R., Gamba-Vitalo C., Maier M., Jayaprakash K.N., Jayaraman M., Rajeev K.G., Manoharan M., Koteliansky V., Röhl I., Leshchiner E.S., Langer R., Anderson D.G. Development of lipidoid-siRNA formulations for systemic delivery to the liver. Mol. Therapy. 2009;17(5):872–879. https://doi.org/10.1038/mt.2009.36

Akinc A., Zumbuehl A., Goldberg M., Leshchiner E.S., Busini V., Hossain N., Bacallado S.A., Nguyen D.N., Fuller J., Alvarez R., Borodovsky A., Borland T., Constien R., De Fougerolles A., Dorkin J.R., Jayaprakash K.N., Jayaraman M., John M., Koteliansky V., Manoharan M., Nechev L., Qin J., Racie T., Raitcheva D., Rajeev K.G., Sah D.W.Y., Soutschek J., Toudjarska I., Vornlocher H.P., Zimmermann T.S., Langer R., Anderson D.G. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 2008;26:561–569. https://doi.org/10.1038/nbt1402

Love K.T., Mahon K.P., Levins C.G., Whitehead K.A., Querbes W., Dorkin J.R., Qin J., Cantley W., Qin L.L., Racie T., Frank-Kamenetsky M., Yip K.N., Alvarez R., Sah D.W.Y., De Fougerolles A., Fitzgerald K., Koteliansky V., Akinc A., Langer R., Anderson D.G. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl. Acad. Sci. USA. 2010;107(5): 1864–1869. https://doi.org/10.1073/pnas.0910603106

Turnbull I.C., Eltoukhy A.A., Fish K.M., Nonnenmacher M., Ishikawa K., Chen J., Hajjar R.J., Anderson D.G., Costa K.D. Myocardial delivery of lipidoid nanoparticle carrying modRNA induces rapid and transient expression. Mol. Therapy. 2016;24(1):66–75. https://doi.org/10.1038/mt.2015.193

Jiang C., Mei M., Li B., Zhu X., Zu W., Tian Y., Wang Q., Guo Y., Dong Y., Tan X. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 2017;27:440–443. https://doi.org/10.1038/cr.2017.16

Liu S., Cheng Q., Wei T., Yu X., Johnson L.T., Farbiak L., Siegwart D.J. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 2021;20:701–710. https://doi.org/10.1038/s41563-020-00886-0

Li B., Luo X., Deng B., Wang J., McComb D.W., Shi Y., Gaensler K.M.L., Tan X., Dunn A.L., Kerlin B.A., Dong Y. An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo. Nano Lett. 2015;15(12): 8099–8107. https://doi.org/10.1021/acs.nanolett.5b03528

Zeng C., Hou X., Yan J., Zhang C., Li W., Zhao W., Du S., Dong Y. Leveraging mRNA Sequences and Nanoparticles to Deliver SARS-CoV-2 Antigens In Vivo. Adv. Mater. 2020;32(40):е2004452. https://doi.org/10.1002/adma.202004452

Gindy M.E., Feuston B., Glass A., Arrington L., Haas R.M., Schariter J., Stirdivant S.M. Stabilization of Ostwald ripening in low molecular weight amino lipid nanoparticles for systemic delivery of siRNA Therapeutics. Mol. Pharm. 2014;11(11):4143–4153. https://doi.org/10.1021/mp500367k

Suzuki Y., Hyodo K., Tanaka Y., Ishihara H. siRNA-lipid nanoparticles with long-term storage stability facilitate potent gene-silencing in vivo. J. Controll. Release. 2015;220:44–50. https://doi.org/10.1016/J.JCONREL.2015.10.024

Suzuki Y., Hyodo K., Suzuki T., Tanaka Y., Kikuchi H., Ishihara H. Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates. Int. J. Pharm. 2017;519(1-2):34–43. https://doi.org/10.1016/j.ijpharm.2017.01.016

Lokugamage M.P., Sago C.D., Gan Z., Krupczak B.R., Dahlman J.E. Constrained Nanoparticles Deliver siRNA and sgRNA to T Cells In Vivo without Targeting Ligands. Adv. Mater. 2019;31(41):е1902251. https://doi.org/10.1002/adma.201902251

Ni H., Hatit M.Z.C., Zhao K., Loughrey D., Lokugamage M.P., Peck H.E., Del Cid A., Muralidharan A., Kim Y.T., Santangelo P.J., Dahlman J.E. Piperazinederived lipid nanoparticles deliver mRNA to immune cells in vivo. Nat. Commun. 2022;13(1):4766. https://doi.org/10.1038/s41467-022-32281-5

Miao L., Li L., Huang Y., Delcassian D., Chahal J., Han J., Shi Y., Sadtler K., Gao W., Lin J., Doloff J.C., Langer R., Anderson D.G. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 2019;37:1174–1185. https://doi.org/10.1038/s41587-019-0247-3

Hou X., Zhang X., Zhao W., Zeng C., Deng B., McComb D.W., Du S., Zhang C., Li W., Dong Y. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 2020;15(1):41–46. https://doi.org/10.1038/s41565-019-0600-1

Ho W., Gao M., Li F., Li Z., Zhang X.Q., Xu X. NextGeneration Vaccines: Nanoparticle-Mediated DNA and mRNA Delivery. Adv. Healthc. Mater. 2021;10(8):e2001812. https://doi.org/10.1002/adhm.202001812

Knezevic I., Liu M.A., Peden K., Zhou T., Kang H.N. Development of mRNA Vaccines: Scientific and Regulatory Issues. Vaccines (Basel). 2021;9(2):81. https://doi.org/10.3390/VACCINES9020081

Bauman J., Burris H., Clarke J., Patel M., Cho D., Gutierrez M., Julian R., Scott A., Cohen P., Frederick J., Robert-Tissot C., Zhou H., Mody K., Keating K., Meehan R., Gainor J. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. ImmunoTher. Cancer. 2020;8(Suppl.3):0798. https://doi.org/10.1136/JITC-2020-SITC2020.0798.

Soens M., Ananworanich J., Hicks B., Lucas K.J., Cardona J., Sher L., Livermore G., Schaefers K., Henry C., Choi A., Avanesov A., Chen R., Du E., Pucci A., Das R., Miller J., Nachbagauer R. A phase 3 randomized safety and immunogenicity trial of mRNA-1010 seasonal influenza vaccine in adults. Vaccine. 2025;50:126847. https://doi.org/10.1016/J.VACCINE.2025.126847

Shaw C., Panther L., August A., Zaks T., Smolenov I., Bart S., Watson M. Safety and immunogenicity of a mRNA-based chikungunya vaccine in a phase 1 doseranging trial. Int. J. Infectious Dis. 2019;79(Suppl. 1):17. https://doi.org/10.1016/j.ijid.2018.11.058

Feldman R.A., Fuhr R., Smolenov I., Ribeiro A. (Mick)., Panther L., Watson M., Senn J.J., Smith M., Almarsson Ӧ., Pujar H.S., Laska M.E., Thompson J., Zaks T., Ciaramella G. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326–3334. https://doi.org/10.1016/J.VACCINE.2019.04.074

Gillmore J.D., Gane E., Taubel J., Kao J., Fontana M., Maitland M.L., Seitzer J., O’Connell D., Walsh K.R., Wood K., Phillips J., Xu Y., Amaral A., Boyd A.P., Cehelsky J.E., McKee M.D., Schiermeier A., Harari O., Murphy A., Kyratsous C.A., Zambrowicz B., Soltys R., Gutstein D.E., Leonard J., Sepp-Lorenzino L., Lebwohl D. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 2021;385(6):493–502. https://doi.org/10.1056/nejmoa2107454

Soroudi S., Jaafari M.R., Arabi L. Lipid nanoparticle (LNP) mediated mRNA delivery in cardiovascular diseases: Advances in genome editing and CAR T cell therapy. J. Controll. Release. 2024;372:113–140. https://doi.org/10.1016/J.JCONREL.2024.06.023

Puthanakit T., Prompetchara E., Gatechompol S., Ketloy C., Thitithanyanont A., Jongkaewwattana A., Buranapraditkun S., Ubolyam S., Kerr S.J., Sophonphan J., Apornpong T., Kittanamongkolchai W., Siwamogsatham S., Sriplienchan S., Patarakul K., Theerawit T., Promsena P., Nantanee R., Manomaisantiphap S., Chokyakorn S., Hong L., Samija M., Montefiori D.C., Gao H., Eaton A., Wijagkanalan W., Alameh M.G., Weissman D., Ruxrungtham K., Tawan M., Sutjarit A., Meepuksom T., Athipunjapong J., Jupimai T., Moonwong J., Nadsasarn R., Khamthi S., Nuncharoen P., Chanpoom Y., Khamkhen P., Narupan N., Thongthip S., Soisoongnern K., Shanyip C., Rachpradit T., Sriphraram K., Somhanwong W., Boondamnern T., Boonnak N., Chomchey N., Tipsuk S., Puttamaswin S., Yewande S., Lertarom P., Uanithirat A., Anuchadbut A., Chanthaburanun S., Tarawat K., Mahanontharit A., Sinthon W., Plakunmonthonw S., Wongmueang S., Dalodom T., Sopa B., Phongam N., Sri-Arunsak A., Chobkarching U., Bouko C., Junseeha S., Phuphalicho B., Pingthaisong P., Khlaiphuengsin A., Pararit P., Eamyoung P., Somjit T., Iampornsin T., Thongchomphunut D., Manopwisedjaroen S., Laopanupong T., Ekronarongchai S., Srisaowakarn C., Jantraphakorn Y., Srisutthisamphan K., Grandin P.V. Phase II prefusion non-stabilised Covid-19 mRNA vaccine randomised study. Sci. Rep. 2024;14(1):2373. https://doi.org/10.1038/s41598-023-49653-6

The authors declare that there are no conflicts of interest present.