Abstract
Introduction. Single-stranded yeast RNA–ascorbic acid complexes are of interest as a class of natural immunomodulatory systems combining activation of innate immune pattern-recognition receptors with redox-modulating and epigenetic effects of vitamin C. Russian studies indicate that such compositions can induce interferon response, stimulate interferon-stimulated genes and show antiviral activity in vitro. However, molecular determinants responsible for interindividual variability of efficacy remain insufficiently characterized.
Objective. To systematize data on the molecular mechanisms of action of single-stranded yeast RNA and ascorbic acid complexes, to identify critical quality attributes associated with immunobiological activity, and to propose a set of potential molecular predictors of efficacy for personalized application.
Material and methods. An analytical review of Russian and international publications devoted to yeast RNA, RNA interferon inducers, innate immune receptors, interferon-stimulated genes, redox regulation, and critical quality attributes of RNA-containing compositions was performed. Publications from PubMed, Scopus, Web of Science, eLibrary, as well as recent Russian works of 2025–2026 on RNA pathogen-associated molecular patterns, synergism of ascorbic acid and RNA inducers, pharmaceutical chemistry of yeast RNA–ascorbate complexes, and antiviral activity in the rabies model were analyzed.
Results. The efficacy of single-stranded yeast RNA–ascorbic acid complexes is determined by two factor groups: properties of the composition itself and host-response characteristics. The most important quality attributes include RNA source and fraction profile, chain length, proportion of double-stranded regions, impurity profile, ascorbic acid stability, level of degradation products, and physicochemical parameters of the medium. At the biological-response level, promising predictors include baseline expression of TLR3, TLR7/8, DDX58/RIG-I, IFIH1/MDA5, activity of the MAVS–IRF3/7 axis, intensity of type I interferon induction and interferon-stimulated genes, as well as cellular redox status. A conceptual framework is proposed linking control of critical quality attributes with profiling of molecular response and patient stratification.
Conclusion. Single-stranded yeast RNA–ascorbic acid complexes should be considered not only as broad-spectrum immunomodulators, but also as a platform for personalized immunomodulation. The most promising research direction is integration of pharmaceutical quality control with assessment of molecular predictors of response, including PRR profile, interferon signature and redox biomarkers. This approach may provide a rational basis for developing new antiviral and adjuvant agents.
Keywords
Authors and affiliations
https://elibrary.ru/ujqhae
T.V. Potupchik(1), V.V. Ermolaev(2), S.V. Generalov(3), Yu.S. Alikin(4), L.S. Evert(5), D.V. Kurbanova(6), A.S. Shevchuk(6), L.S. Omarova(6)
1-Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University
named after Professor V.F. Voyno-Yasenetsky” of the Ministry of Health of the Russian Federation, Partizana Zheleznyaka St., 1,
Krasnoyarsk, 660022, Russian Federation; 2-State Research Center of Virology and Biotechnology “Vector” of the Federal Service for Surveillance
on Consumer Rights Protection and Human Wellbeing, Koltsovo, Novosibirsk Region, 630559, Russian Federation; 3Federal State Scientific Institution “Russian Anti-Plague Research Institute ‘Microbe’” of the Federal Service for Surveillance on Consumer Rights Protection
and Human Wellbeing, Universitetskaya St., 46, Saratov, 410005, Russian Federation; 4-LLC “NPO Evolution of Nature”,
Voskhod St., 20/1 premises 1.2, Novosibirsk, 630102, Russian Federation; 5-Federal State Budgetary Educational Institution
of Higher Education “Khakass State University named after N.F. Katanov” of the Ministry of Science and Higher Education,
20/1 premises 1.2, Abakan, 20/1 premises 1.2, 655017, Russian Federation; ⁶-Pirogov Russian National Research Medical University
of the Ministry of Health of the Russian Federation, Ostrovityanova str., 1, building 6, Moscow, 117513, Russian Federation
References
1. Потупчик Т.В., Аликин Ю.С., Генералов С.В. и др. Молекулярные паттерны РНК-патогенов и иммунный ответ на экзогенные РНК: механизмы распознавания и терапевтический потенциал. Молекулярная медицина. 2026; 24 (1): 31–8. DOI: 10.29296/24999490-2026-01-04. [Potupchik T.V., Alikin Yu.S., Generalov S.V. et al. Molecular patterns of RNA pathogens and immune response to exogenous RNA: recognition mechanisms and therapeutic potential. Molekulyarnaya meditsina. 2026; 24 (1): 31–8 (in Russian)].
2. Потупчик Т.В., Кучеренко А.М., Генералов С.В. и др. Иммуностимулирующие РНК Saccharomyces cerevisiae: структура, рецепторы врожденного иммунитета и молекулярные механизмы действия. Вопросы биологической, медицинской и фармацевтической химии. 2026; 29 (3): 50–6. DOI: 10.29296/25877313-2026-03-00. [Potupchik T.V., Kucherenko A.M., Generalov S.V. et al. Immunostimulating RNA of Saccharomyces cerevisiae: structure, innate immune receptors and molecular mechanisms of action. Problems of biological, medical and pharmaceutical chemistry. 2026; 29 (3): 50–6 (in Russian)].
3. Потупчик Т.В., Аликин Ю.С., Генералов С.В. и др. Синергизм аскорбиновой кислоты и РНК-индукторов интерферона в активации противовирусного иммунитета: молекулярные механизмы и терапевтические перспективы. Молекулярная медицина. 2025; 23 (6): 76–83. DOI: 10.29296/24999490-2025-06-10. [Potupchik T.V., Alikin Yu.S., Generalov S.V. et al. Synergism of ascorbic acid and RNA interferon inducers in antiviral immunity activation: molecular mechanisms and therapeutic perspectives. Molekulyarnaya meditsina. 2025; 23 (6): 76–83 (in Russian)].
4. Потупчик Т.В., Кучеренко А.М., Генералов С.В. и др. Фармацевтические аспекты разработки комплексов одноцепочечной дрожжевой РНК с аскорбиновой кислотой. Часть 1. Физико-химические характеристики и критические атрибуты качества. Вопросы биологической, медицинской и фармацевтической химии. 2026; 29 (4): 3–13. DOI: 10.29296/25877313-2026-04-01. [Potupchik T.V., Kucherenko A.M., Generalov S.V. et al. Pharmaceutical aspects of development of complexes of single-stranded yeast RNA with ascorbic acid. Part 1. Physicochemical characteristics and critical quality attributes. Problems of biological, medical and pharmaceutical chemistry. 2026; 29 (4): 3–13. (in Russian)].
5. Генералов С.В., Перевозников Д.А., Абрамова Е.Г. и др. Противовирусная активность препарата на основе комплекса одноцепочечной высокополимерной РНК в отношении вируса бешенства in vitro. Вопросы биологической, медицинской и фармацевтической химии. 2025; 28 (8): 38–44. DOI: 10.29296/25877313-2025-08-05. [Generalov S.V., Perevoznikov D.A., Abramova E.G. et al. Antiviral activity of a drug based on a complex of single-stranded high-polymer RNA against rabies virus in vitro. Problems of biological, medical and pharmaceutical chemistry. 2025; 28 (8): 38–44 (in Russian)].
6. Потупчик Т.В., Генералов С.В., Акаева А.В. и др. Новые стратегии постэкспозиционной профилактики бешенства: роль иммуномодулирующих и таргетных молекулярных технологий в персонализированной медицине. Молекулярная медицина. 2025; 23 (5): 49–57. DOI: 10.29296/24999490-2025-05-06. [Potupchik T.V., Generalov S.V., Akaeva A.V. et al. Novel strategies for post-exposure rabies prophylaxis: the role of immunomodulatory and targeted molecular technologies in personalized medicine. Molekulyarnaya meditsina. 2025; 23 (5): 49–57 (in Russian)].
7. Подгорный В.Ф., Аликин Ю.С., Лебедев Л.Р. и др. Способ получения двуцепочечной рибонуклеиновой кислоты (дсРНК) из клеток дрожжей Saccharomyces cerevisiae. Патент РФ №2558256C1. 2015. [Podgorny V.F., Alikin Yu.S., Lebedev L.R. et al. Method of obtaining double-stranded ribonucleic acid (dsRNA) from yeast Saccharomyces cerevisiae cells. RF Patent No. 2558256C1. 2015 (in Russian)].
8. Schlee M., Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016; 16 (9): 566–80. DOI: 10.1038/nri.2016.78
9. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity. Nat Immunol. 2010; 11 (5): 373–84. DOI: 10.1038/ni.1863
10. Alexopoulou L., Holt A.C., Medzhitov R., Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413 (6857): 732–8. DOI: 10.1038/35099560
11. Heil F., Hemmi H., Hochrein H. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303 (5663): 1526–9. DOI: 10.1126/science.1093620
12. Yoneyama M., Fujita T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev. 2009; 227 (1): 54–65. DOI: 10.1111/j.1600-065X.2008.00727.x
13. Kato H., Takeuchi O., Sato S. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006; 441 (7089): 101–5. DOI: 10.1038/nature04734
14. Rehwinkel J., Gack M.U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020; 20 (9): 537–51. DOI: 10.1038/s41577-020-0288-3
15. Luan X., Wang Y., Yue R. et al. Innate immune responses to RNA: sensing and signaling. Front Immunol. 2024; 15: 1287940. DOI: 10.3389/fimmu.2024.1287940
16. Schneider W.M., Chevillotte M.D., Rice C.M. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014; 32: 513–45. DOI: 10.1146/annurev-immunol-032713-120231
17. Carr A.C., Maggini S. Vitamin C and immune function. Nutrients. 2017; 9 (11): 1211. DOI: 10.3390/nu9111211
18. Ang A., Pullar J.M., Currie M.J., Vissers M.C.M. Vitamin C and immune cell function in inflammation and cancer. Biochem Soc Trans. 2018; 46 (5): 1147–59. DOI: 10.1042/BST20180169
19. Huijskens M.J., Walczak M., Koller N. et al. Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. J Leukoc Biol. 2014; 96 (6): 1165–75. DOI: 10.1189/jlb.1TA0214-121RR
20. Manning J., Mitchell B., Appadurai D.A. et al. Vitamin C promotes maturation of T-cells. Antioxid Redox Signal. 2013; 19 (17): 2054–2067. DOI: 10.1089/ars.2012.4988
21. Blaschke K., Ebata K.T., Karimi M.M. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature. 2013; 500 (7461): 222–6. DOI: 10.1038/nature12362
22. Cimmino L., Dolgalev I., Wang Y. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017; 170 (6): 1079–95. DOI: 10.1016/j.cell.2017.07.032
23. Kawai T., Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011; 34 (5): 637–50. DOI: 10.1016/j.immuni.2011.05.006
24. Ren Z., Ding T., Zuo Z. et al. Regulation of MAVS expression and signaling function in the antiviral innate immune response. Front Immunol. 2020; 11: 1030. DOI: 10.3389/fimmu.2020.01030
25. Brisse M., Ly H. Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front Immunol. 2019; 10: 1586. DOI: 10.3389/fimmu.2019.01586
26. West A.P., Shadel G.S., Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011; 11 (6): 389–402. DOI: 10.1038/nri2975
27. Mills E.L., Kelly B., O’Neill L.A.J. Mitochondria are the powerhouses of immunity. Nat Immunol. 2017; 18 (5): 488–98. DOI: 10.1038/ni.3704
28. Шрайнер Е.В., Быстрова В.И., Покушалов Е.А. и др. Глутатион: ключевая молекула редокс-гомеостаза и возможности ее нутриентной и метаболической регуляции (обзор литературы). Молекулярная медицина. 2025; 23 (5): 79–88. DOI: 10.29296/24999490-2025-05-09. [Shrayner E.V., Bystrova V.I., Pokushalov E.A. et al. Glutathione: a key molecule of redox homeostasis and its potential for nutritional and metabolic regulation (a review of the literature). Molecular Medicine. 2025; 23 (5): 79–88 (in Russian)].
29. Даниленко Е.Д., Белкина А.О., Сысоева Г.М. Создание лекарственных препаратов на основе высокополимерных двуспиральных РНК для противовирусной и противоопухолевой терапии. Биомедицинская химия. 2019; 65 (4): 277–93. DOI: 10.1134/S1990750819040036. [Danilenko E.D., Belkina A.O., Sysoeva G.M. Development of drugs based on high-polymeric double-stranded RNA for antiviral and antitumor therapy. Biomedical Chemistry. 2019; 65 (4): 277–93 (in Russian)].
30. Bateneva N.A., Gamaley S.G., Danilenko E.D. et al. Stimulating effect of double-stranded yeast RNA on the activity of interferon system genes. Medical Immunology (Russia). 2021; 22 (6): 1155–62. DOI: 10.15789/1563-0625-SEO-2082
31. Kayesh M.E.H., Kohara M., Tsukiyama-Kohara K. TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview. Front Microbiol. 2023; 14: 1249718. DOI: 10.3389/fmicb.2023.1249718
32. Pardi N., Hogan M.J., Porter F.W. et al. mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov. 2018; 17 (4): 261–79. DOI: 10.1038/nrd.2017.243