Academic Journal
Dual Ionizable Lipids (ALC0315 and SM102) in a Novel Lipid Nanoparticle Formulation Enhance In Vivo Delivery and Time-Dependent Expression of Messenger RNA and Self-Amplifying RNA.
| Τίτλος: | Dual Ionizable Lipids (ALC0315 and SM102) in a Novel Lipid Nanoparticle Formulation Enhance In Vivo Delivery and Time-Dependent Expression of Messenger RNA and Self-Amplifying RNA. |
|---|---|
| Συγγραφείς: | Kunyk D; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Vasileva O; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Bespalov M; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Dzharullaeva A; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia., Mazunina E; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia., Chubarova A; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Seliverstov M; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Smirnykh D; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Shevyrev D; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Shtraus S; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Kozlova A; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Subcheva E; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Kleymenov D; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia., Bykonia E; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia., Baranov MV; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Logunov DY; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia., Gushchin VА; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia.; Sechenov First Moscow State Medical University, Moscow, Russia., Ivanov R; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Reshetnikov V; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia., Skvortsov IA; Translational Medicine Research Center, Sirius University of Science and Technology, Sochi, Russia. |
| Πηγή: | ChemMedChem [ChemMedChem] 2026 Jun 15; Vol. 21 (11), pp. e70335. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 101259013 Publication Model: Print Cited Medium: Internet ISSN: 1860-7187 (Electronic) Linking ISSN: 18607179 NLM ISO Abbreviation: ChemMedChem Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Weinheim, Germany : Wiley-VCH, c2006- |
| Ιατρικοί όροι (MeSH): | Nanoparticles*/chemistry , RNA, Messenger*/genetics , RNA, Messenger*/metabolism , RNA, Messenger*/chemistry , Lipids*/chemistry, Animals ; Particle Size ; Humans ; Mice ; Liposomes |
| Περίληψη: | This study introduces a novel five-component LNP formulation incorporating ionizable lipid combination ALC-0315 and SM-102 with cholesterol, DSPC, and DMG-PEG-2000. LNP-5 was designed for efficient delivery of mRNA and saRNA. We employed a Design of Experiments approach and microfluidics to optimize the formulation parameters, achieving high encapsulation efficiencies (>80%) for both RNA types. Physicochemical characterization by dynamic light scattering confirmed a controlled size (80-120 nm) and low polydispersity (<0.2). The morphology of investigated LNP-5 was studied by STEM in comparison with LNP-4 (with SM-102 or ALC-0315). Notably, LNP-5 demonstrated superior in vivo mRNA delivery efficiency and enhanced target protein expression compared to conventional LNP-4. The study compares the in vivo performance of mRNA and saRNA platforms formulated in novel LNP-5 lipid nanoparticles containing dual ionizable lipids. While LNP-mRNA delivery provides rapid and intense but transient reporter expression, LNP-saRNA mediates a gradual increase in protein production, peaking at day 7 post-injection. Quantitative RT-PCR analysis reveals superior saRNA persistence and a 4.3-fold higher copy number relative to mRNA by day 7, confirming active intracellular replication of the saRNA platform. These findings demonstrate that LNP-5 efficiently delivers both platforms, with saRNA offering a more sustained therapeutic window due to its self-amplifying properties. (© 2026 Wiley‐VCH GmbH.) |
| References: | K. Paunovska, D. Loughrey, and J. E. Dahlman, “Drug Delivery Systems for RNA Therapeutics,” Nature Reviews Genetics 23 (2022): 265–280. G. B. Schober, S. Story, and D. P. Arya, “A Careful Look at Lipid Nanoparticle Characterization: Analysis of Benchmark Formulations for Encapsulation of RNA Cargo Size Gradient,” Scientific Reports 14 (2024): 2403. B. B. Mendes, J. Conniot, A. Avital, et al., “Nanodelivery of Nucleic Acids,” Nature Reviews Methods Primers 2 (2022): 24. C. H. Albertsen, J. A. Kulkarni, D. Witzigmann, et al., “The Role of Lipid Components in Lipid Nanoparticles for Vaccines and Gene Therapy,” Advanced Drug Delivery Reviews 188 (2022): 114416. T.‐L. Hwang, I. A. Aljuffali, C.‐F. Lin, et al., “Cationic Additives in Nanosystems Activate Cytotoxicity and Inflammatory Response of Human Neutrophils: Lipid Nanoparticles Versus Polymeric Nanoparticles,” International Journal of Nanomedicine 10 (2015): 371–385. Y. Lee, M. Jeong, J. Park, et al., “Immunogenicity of Lipid Nanoparticles and Its Impact on the Efficacy of mRNA Vaccines and Therapeutics,” Experimental and Molecular Medicine 55 (2023): 2085–2096. N. B. Hamilton, S. Arns, M. Shelley, et al., “Calculating Apparent pKa Values of Ionizable Lipids in Lipid Nanoparticles,” Molecular Pharmaceutics 22 (2025): 588–593. I. M. Hafez and P. R. Cullis, “Roles of Lipid Polymorphism in Intracellular Delivery,” Advanced Drug Delivery Reviews 47 (2001): 139–148. F. P. Polack, S. J. Thomas, N. Kitchin, et al., “Safety and Efficacy of the BNT162b2 mRNA Covid‐19 Vaccine,” New England Journal of Medicine 383 (2020): 2603–2615. L. R. Baden, H. M. E. Sahly, B. Essink, et al., “Efficacy and Safety of the mRNA‐1273 SARS‐CoV‐2 Vaccine,” New England Journal of Medicine 384 (2021): 403–416. B. Binici, Z. Rattray, A. Zinger, and Y. Perrie, “Exploring the Impact of Commonly Used Ionizable and Pegylated Lipids on mRNA‐LNPs: A Combined In Vitro and Preclinical Perspective,” Journal of Controlled Release 377 (2025): 162–173. L. Zhang, K. R. More, A. Ojha, et al., “Effect of mRNA‐LNP Components of Two Globally‐Marketed COVID‐19 Vaccines on Efficacy and Stability,” npj Vaccines 8 (2023): 156. Y. Ren, L. Lin, M. Abdallah, et al., “Impact of Ionizable Lipid Type on the Pharmacokinetics and Biodistribution of mRNA‐Lipid Nanoparticles After Intravenous and Subcutaneous Injection,” Journal of Controlled Release 384 (2025): 113945. K. J. Hassett, K. E. Benenato, E. Jacquinet, et al., “Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines,” Molecular Therapy ‐ Nucleic Acids 15 (2019): 1–11. M. D. Buschmann, M. J. Carrasco, S. Alishetty, et al., “Nanomaterial Delivery Systems for mRNA Vaccines,” Vaccines 9 (2021): 65. A. M. Jörgensen, R. Wibel, and A. Bernkop‐Schnürch, “Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients,” Small 19 (2023): 2206968. A. K. Blakney, P. F. McKay, B. I. Yus, et al., “Inside Out: Optimization of Lipid Nanoparticle Formulations for Exterior Complexation and In Vivo Delivery of saRNA,” Gene Therapy 26 (2019): 363–372. A. K. Blakney, P. F. McKay, B. Ibarzo, and etal Yus, “The Skin You Are in: Design‐of‐Experiments Optimization of Lipid Nanoparticle Self‐Amplifying RNA Formulations in Human Skin Explants,” ACS Nano 13 (2019): 5920–5930. D. Kunyk, M. Plotnikova, M. Bespalov, et al., “The Interplay Between Therapeutic Self‐Amplifying RNA and the Innate Immune System: Balancing Efficiency and Reactogenicity,” International Journal of Molecular Sciences 26 (2025): 8986. H. Azizi, T. M. Renner, G. Agbayani, et al., “Self‐Amplifying RNAs Generated with the Modified Nucleotides 5‐Methylcytidine and 5‐Methyluridine Mediate Strong Expression and Immunogenicity In Vivo,” NAR Molecular Medicine 1 (2024): ugae004. A. K. Blakney, S. Ip, and A. J. Geall, “An Update on Self‐Amplifying mRNA Vaccine Development,” Vaccines 9 (2021): 97. A. J. Geall, A. Verma, G. R. Otten, et al., “Nonviral Delivery of Self‐Amplifying RNA Vaccines,” Proceedings of the National Academy of Sciences 109 (2012): 14604–14609. N. T. Hồ, S. G. Hughes, V. T. Ta, et al., “Safety, Immunogenicity and Efficacy of the Self‐Amplifying mRNA ARCT‐154 COVID‐19 Vaccine: Pooled Phase 1, 2, 3a and 3b Randomized, Controlled Trials,” Nature Communications 15 (2024): 4081. A. Ryapolova, D. Shevyrev, A. Tsvetkova, et al., “Enhanced Antitumor Effect of Oncolytic Virotherapy Combined with mRNA‐Encoded Immunoadjuvants in Colorectal Carcinoma (CT26) Tumor Model,” Applied Biosciences 5 (2026): 1. B. D. Barbieri, D. J. Peeler, K. Samnuan, et al., “The Role of Helper Lipids in Optimising Nanoparticle Formulations of Self‐Amplifying RNA,” Journal of Controlled Release 374 (2024): 280–292. D. A. Estabrook, L. Huang, O. R. Lucchese, et al., “Buffer Optimization of siRNA‐Lipid Nanoparticles Mitigates Lipid Oxidation and RNA‐Lipid Adduct Formation,” Nature Communications 16 (2025): 8380. J. Di, Z. Du, K. Wu, et al., “Biodistribution and Non‐Linear Gene Expression of mRNA LNPs Affected by Delivery Route and Particle Size,” Pharmaceutical Research 39 (2022): 105. M. Kumar, P. Kulkarni, S. Liu, et al., “Nanoparticle Biodistribution Coefficients: A Quantitative Approach for Understanding the Tissue Distribution of Nanoparticles,” Advanced Drug Delivery Reviews 194 (2023): 114708. D. Omata, E. Kawahara, L. Munakata, et al., “Effect of Anti‐PEG Antibody on Immune Response of mRNA‐Loaded Lipid Nanoparticles,” Molecular Pharmaceutics 21 (2024): 5672–5680. B. Lew, S. Chhabra, J. A. Lewis, et al., “Surface Plasmon Resonance Based Binding Characterization for Screening RNA‐Loaded Lipid Nanoparticles (LNPs): Exploring Species Cross‐Reactivity in LNP–Apolipoprotein E Interactions,” Molecular Pharmaceutics 22 (2025): 4587–4596. M. Hussain, A. Ferguson‐Ugorenko, R. Macfarlane, et al., “Mind the Age Gap: Expanding the Age Window for mRNA Vaccine Testing in Mice,” Vaccines 13 (2025): 370. O. Escalona‐Rayo, Y. Zeng, R. A. Knol, et al., “In Vitro and In Vivo Evaluation of Clinically‐Approved Ionizable Cationic Lipids Shows Divergent Results Between mRNA Transfection and Vaccine Efficacy,” Biomedicine and Pharmacotherapy 165 (2023): 115065. P. R. Cullis and M. J. Hope, “Lipid Nanoparticle Systems for Enabling Gene Therapies,” Molecular Therapy 25 (2017): 1467–1475. K. Wu, F. Xu, Y. Dai, et al., “Characterization of mRNA‐LNP Structural Features and Mechanisms for Enhanced mRNA Vaccine Immunogenicity,” Journal of Controlled Release 376 (2024): 1288–1299. C. Tan, S. F. Hosseini, and S. M. Jafari, “Cubosomes and Hexosomes as Novel Nanocarriers for Bioactive Compounds,” Journal of Agricultural and Food Chemistry 70 (2022): 1423–1437. B. Binici, Z. Rattray, and Y. Perrie, “A Comparative Study of Cationic Lipid‐Enriched LNPs for mRNA Vaccine Delivery,” International Journal of Pharmaceutics 682 (2025): 125941. S. S. Shishani and P. R. DeFelicis, “Impact of Lipid Composition on Vesicle Protein Adsorption: A BSA Case Study,” ACS Omega 9 (2024): 11211–11220. G. Sahay, K. W. Querbes, C. Alabi, et al., “Image‐Based Analysis of Lipid Nanoparticle–Mediated siRNA Delivery, Intracellular Trafficking and Endosomal Escape,” Nature Biotechnology 31 (2013): 653–658. Y. Gong, D. Yong, G. Liu, et al., “A Novel Self‐Amplifying mRNA with Decreased Cytotoxicity and Enhanced Protein Expression by Macrodomain Mutations,” Advanced Science 11 (2024): 2402936. I. C. Casmil, J. J. Friesen, N. V. Bathula, et al., “Divergent Delivery and Expression Kinetics of Lipid and Polymeric Nanoparticles Across mRNA Modalities,” Advanced Science 12 (2025): e2408907. J. E. McGee, J. R. Kirsch, D. Kenney, et al., “Complete Substitution with Modified Nucleotides in Self‐Amplifying RNA Suppresses the Interferon Response and Increases Potency,” Nature Biotechnology 43 (2025): 720–726. Z. Wang, Y. Chen, H. Wu, et al., “Intravenous Administration of IL‐12 Encoding Self‐Replicating RNA‐Lipid Nanoparticle Complex Leads to Safe and Effective Antitumor Responses,” Scientific Reports 14 (2024): 7366. Z. Sun, Y. Liu, H. Zhang, et al., “Next‐Generation saRNA Platforms: Systematic Screening and Engineering Enhances Superior Protein Expression and Organ‐Specific Targeting for RNA Therapeutics,” Biorxiv (2025): 2025–2003. N. Yoshioka, E. Gros, H.‐R. Li, et al., “Efficient Generation of Human iPSCs by a Synthetic Self‐Replicative RNA,” Cell Stem Cell 13 (2013): 246–254. V. Reshetnikov, I. Terenin, G. Shepelkova, et al., “Untranslated Region Sequences and the Efficacy of mRNA Vaccines Against Tuberculosis,” International Journal of Molecular Sciences 25 (2024): 888. A. Kozlova, I. Pateev, G. Shepelkova, et al., “A Cap‐Optimized mRNA Encoding Multiepitope Antigen ESAT6 Induces Robust Cellular and Humoral Immune Responses Against Mycobacterium Tuberculosis,” Vaccines 12 (2024): 1267. |
| Grant Information: | "Sirius" Federal Territory "Scientific and technological development of the "Sirius" Federal Territory" |
| Contributed Indexing: | Keywords: SM‐102 and ALC‐0315; in vivo; lipid nanoparticles; mRNA; saRNA |
| Substance Nomenclature: | 0 (RNA, Messenger) 0 (Lipids) 0 (Lipid Nanoparticles) 0 (Liposomes) |
| Entry Date(s): | Date Created: 20260609 Date Completed: 20260612 Latest Revision: 20260805 |
| Update Code: | 20260806 |
| DOI: | 10.1002/cmdc.70335 |
| PMID: | 42264921 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!