1,140
Views
0
CrossRef citations to date
0
Altmetric
Review

Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out

&
Pages 175-187 | Received 23 Aug 2022, Accepted 22 Dec 2022, Published online: 01 Jan 2023

References

  • Myles L, Church TD. An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies. Cytotherapy. 2022;24(3):344–355.
  • Kulkarni JA, Witzigmann D, Thomson SB, et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. 2021;16(6):630–643.
  • Li Z, Zhang L, Jiang K, et al. Biosafety assessment of delivery systems for clinical nucleic acid therapeutics. Biosaf Health. 2022;4(2):105–117.
  • Jones KL, Drane D, Gowans EJ. Long-term storage of DNA-free RNA for use in vaccine studies. Biotechniques. 2007;43(5):675–681.
  • Probst J, Weide B, Scheel B, et al. Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent. Gene Ther. 2007;14(15):1175–1180.
  • Blakney AK, McKay PF, Yus BI, et al. Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA. Gene Ther. 2019;26(9):363–372.
  • Blakney AK, Ip S, Geall AJ. An update on self-amplifying mRNA vaccine development. Vaccines (Basel). 2021;9(2):97.
  • Ricciardi AS, Bahal R, Farrelly JS, et al. In utero nanoparticle delivery for site-specific genome editing. Nat Commun. 2018;9(1):1–11.
  • Kowalski PS, Rudra A, Miao L, et al. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol Ther. 2019;27(4):710–728.
  • Dimitriadis GJ. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature. 1978;274(5674):923–924.
  • Felgner PL, Gadek TR, Holm M, et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Nat Acad Sci. 1987;84(21):7413–7417.
  • Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Nat Acad Sci. 1989;86(16):6077–6081.
  • Kauffman KJ, Mir FF, Jhunjhunwala S, et al. Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo. Biomaterials. 2016;109:78–87.
  • Patel S, Ashwanikumar N, Robinson E, et al. Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA. Nano Lett. 2017;17(9):5711–5718.
  • Irwin A, Nkengasong J. What it will take to vaccinate the world against COVID-19. Nature. 2021;592(7853):176–178.
  • Zhang -N-N, X-F L, Deng Y-Q, et al. A thermostable mRNA vaccine against COVID-19. Cell. 2020;182(5):1271–1283. e16.
  • Zhang J, Shrivastava S, Cleveland RO, et al. Lipid-mRNA nanoparticle designed to enhance intracellular delivery mediated by shock waves. ACS Appl Mater Interfaces. 2019;11(11):10481–10491.
  • Buyens K, Demeester J, De Smedt SS, et al. Elucidating the encapsulation of short interfering RNA in PEGylated cationic liposomes. Langmuir. 2009;25(9):4886–4891.
  • Jahn A, Vreeland WN, Gaitan M, et al. Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J Am Chem Soc. 2004;126(9):2674–2675.
  • Evers MJ, Kulkarni JA, van der Meel R, et al. State‐of‐the‐art design and rapid‐mixing production techniques of lipid nanoparticles for nucleic acid delivery. Small Methods. 2018;2(9):1700375.
  • Self WH, Tenforde MW, Rhoads JP, et al. Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions—United States, March–August 2021. Morbidity Mortality Weekly Rep. 2021;70(38):1337.
  • Schoenmaker L, Witzigmann D, Kulkarni JA, et al. mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability. Int J Pharm. 2021;601:120586.
  • Ball RL, Bajaj P, Whitehead KA. Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization. Int J Nanomedicine. 2017;12:305.
  • Zhao P, Hou X, Yan J, et al. Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact Mater. 2020;5(2):358–363.
  • Kon E, Elia U, Peer D. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr Opin Biotechnol. 2022;73:329–336.
  • Chen J, Chen J, Xu Q. Current developments and challenges of mRNA vaccines. Annu Rev Biomed Eng. 2022;24:85–109.
  • Ghaemmaghamian Z, Zarghami R, Walker G, et al. Stabilizing vaccines via drying: quality by design considerations. Adv Drug Deliv Rev. 2022;187:114313.
  • Hu B, Li B, Li K, et al. Thermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia. Sci Adv. 2022;8(7):eabm1418.
  • De A, Ko YT. Single pot organic solvent-free thermocycling technology for siRNA-ionizable LNPs: a proof-of-concept approach for alternative to microfluidics. Drug Deliv. 2022;29(1):2644–2657.
  • Salminen H, Ankenbrand J, Zeeb B, et al. Influence of spray drying on the stability of food-grade solid lipid nanoparticles. Food Res Int. 2019;119:741–750.
  • Pascolo S. Synthetic messenger RNA-based vaccines: from scorn to hype. Viruses. 2021;13(2):270.
  • Pascolo S. Vaccination with messenger RNA (mRNA). Toll-like receptors (TLRs) and innate immunity. 2008:221–235.
  • Wayment-Steele HK, Kim DS, Choe CA, et al. Theoretical basis for stabilizing messenger RNA through secondary structure design. Nucleic Acids Res. 2021;49(18):10604–10617.
  • Crommelin DJ, Anchordoquy TJ, Volkin DB, et al. Addressing the cold reality of mRNA vaccine stability. J Pharm Sci. 2021;110(3):997–1001.
  • Zhang H, Rombouts K, Raes L, et al. Fluorescence‐based quantification of messenger RNA and Plasmid DNA decay kinetics in extracellular biological fluids and cell extracts. Adv Biosyst. 2020;4(5):2000057.
  • Han X, Zhang H, Butowska K, et al. An ionizable lipid toolbox for RNA delivery. Nat Commun. 2021;12(1):1–6.
  • Jiao Y, Xia ZL, Ze LJ, et al. Research Progress of nucleic acid delivery vectors for gene therapy. Biomed Microdevices. 2020;22(1):1–10.
  • Suzuki Y, Hyodo K, Tanaka Y, et al. siRNA-lipid nanoparticles with long-term storage stability facilitate potent gene-silencing in vivo. J Control Release. 2015;220:44–50.
  • Bellino S. COVID-19 vaccines approved in the European Union: current evidence and perspectives. Expert Rev Vaccines. 2021;20(10):1195–1199.
  • Kulkarni JA, Darjuan MM, Mercer JE, et al. On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA. ACS Nano. 2018;12(5):4787–4795.
  • Crawford R, Dogdas B, Keough E, et al. Analysis of lipid nanoparticles by Cryo-EM for characterizing siRNA delivery vehicles. Int J Pharm. 2011;403(1–2):237–244.
  • Eygeris Y, Patel S, Jozic A, et al. Deconvoluting lipid nanoparticle structure for messenger RNA delivery. Nano Lett. 2020;20(6):4543–4549.
  • Leung AK, Hafez IM, Baoukina S, et al. Lipid nanoparticles containing siRNA synthesized by microfluidic mixing exhibit an electron-dense nanostructured core. J Phys Chem C. 2012;116(34):18440–18450.
  • Noor R. mRNA vaccines as an efficient approach for the rapid and robust induction of host immunity against SARS-CoV-2. SN Compreh Clin Med. 2022;4(1):1–7.
  • Papi M, Pozzi D, Palmieri V, et al. Principles for optimization and validation of mRNA lipid nanoparticle vaccines against COVID-19 using 3D bioprinting. Nano Today. 2022;43:101403.
  • Tenchov R, Bird R, Curtze AE, et al. Lipid nanoparticles─ from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 2021;15(11):16982–17015.
  • Pilkington EH, Suys EJ, Trevaskis NL, et al. From influenza to COVID-19: lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases. Acta Biomater. 2021;131:16–40.
  • Rele S. COVID-19 vaccine development during pandemic: gap analysis, opportunities, and impact on future emerging infectious disease development strategies. Hum Vaccin Immunother. 2021;17(4):1122–1127.
  • Arteta MY, Kjellman T, Bartesaghi S, et al. Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles. Proc Nat Acad Sci. 2018;115(15):E3351–E3360.
  • Patel S, Ashwanikumar N, Robinson E, et al. Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA. Nat Commun. 2020;11(1):1–13.
  • Tanaka H, Takahashi T, Konishi M, et al. 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.
  • Leung AK, Tam YYC, Chen S, et al. Microfluidic mixing: a general method for encapsulating macromolecules in lipid nanoparticle systems. J Phys Chem A. 2015;119(28):8698–8706.
  • Brader ML, Williams SJ, Banks JM, et al. Encapsulation state of messenger RNA inside lipid nanoparticles. Biophys J. 2021;120(14):2766–2770.
  • Carrasco MJ, Alishetty S, Alameh M-G, et al. Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration. Commun Biol. 2021;4(1):1–15.
  • Leung AK, Tam YYC, Cullis PR. Lipid nanoparticles for short interfering RNA delivery. Adv Genet. 2014;88:71–110.
  • Shirane D, Tanaka H, Nakai Y, et al. Development of an alcohol dilution–lyophilization method for preparing lipid nanoparticles containing encapsulated siRNA. Biol Pharm Bull. 2018;41(8):1291–1294.
  • Hirota S, de Ilarduya CT, Barron LG, et al. Simple mixing device to reproducibly prepare cationic lipid-DNA complexes (lipoplexes). Biotechniques. 1999;27(2):286–290.
  • Li S, Hu Y, Li A, et al. Payload distribution and capacity of mRNA lipid nanoparticles. Nat Commun. 2022;13(1):1–13.
  • Briuglia M-L, Rotella C, McFarlane A, et al. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Transl Res. 2015;5(3):231–242.
  • Bulbake U, Doppalapudi S, Kommineni N, et al. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9(2):12.
  • Wang C, Siriwardane DA, Jiang W, et al. Quantitative analysis of cholesterol oxidation products and desmosterol in parenteral liposomal pharmaceutical formulations. Int J Pharm. 2019;569:118576.
  • Nakaminami T, Kuwabata S, Yoneyama H. Electrochemical oxidation of cholesterol catalyzed by cholesterol oxidase with use of an artificial electron mediator. Anal Chem. 1997;69(13):2367–2372.
  • Paunovska K, Da Silva Sanchez AJ, Sago CD, et al. Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses. Adv Mater. 2019;31(14):1807748.
  • Brzeska M, Szymczyk K, Szterk A. Current knowledge about oxysterols: a review. J Food Sci. 2016;81(10):R2299–R2308.
  • Kneidl B, Peller M, Winter G, et al. Thermosensitive liposomal drug delivery systems: state of the art review. Int J Nanomedicine. 2014;9:4387.
  • Kulkarni JA, Myhre JL, Chen S, et al. Design of lipid nanoparticles for in vitro and in vivo delivery of plasmid DNA. Nanomedicine. 2017;13(4):1377–1387.
  • Wu Y, Levons J, Narang AS, et al. Reactive impurities in excipients: profiling, identification and mitigation of drug–excipient incompatibility. AAPS PharmSciTech. 2011;12(4):1248–1263.
  • Packer M, Gyawali D, Yerabolu R, et al. A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems. Nat Commun. 2021;12(1):1–11.
  • Terada T, Kulkarni JA, Huynh A, et al. Characterization of lipid nanoparticles containing ionizable cationic lipids using design-of-experiments approach. Langmuir. 2021;37(3):1120–1128.
  • Gaspar R, Coelho F, Silva BF. Lipid-nucleic acid complexes: physicochemical aspects and prospects for cancer treatment. Molecules. 2020;25(21):5006.
  • Cullis PR, Hope MJ. Lipid nanoparticle systems for enabling gene therapies. Mol Ther. 2017;25(7):1467–1475.
  • Ly HH, Daniel S, Soriano SK, et al. Optimization of lipid nanoparticles for saRNA expression and cellular activation using a design-of-experiment approach. Mol Pharm. 2022;19(6): 1892–1905.
  • Komatsu H, Okada S. Ethanol-induced aggregation and fusion of small phosphatidylcholine liposome: participation of interdigitated membrane formation in their processes. Biochimi Biophys Acta (BBA) Biomembr. 1995;1235(2):270–280.
  • Toppozini L, Armstrong CL, Barrett MA, et al. Partitioning of ethanol into lipid membranes and its effect on fluidity and permeability as seen by X-ray and neutron scattering. Soft Matter. 2012;8(47):11839–11849.
  • Kimura N, Maeki M, Sato Y, et al. Development of a microfluidic-based post-treatment process for size-controlled lipid nanoparticles and application to siRNA delivery. ACS Appl Mater Interfaces. 2020;12(30):34011–34020.
  • Keil TW, Merkel OM. Dry powder inhalation of siRNA. Ther Deliv. 2019;10(5):265–267.
  • Karve S, DeRosa F, Heartlein M, et al. Dry powder formulations for messenger RNA. MASSACHUSETTS, USA: Google Patents; 2021.
  • Muralidhara BK, Baid R, Bishop SM, et al. Critical considerations for developing nucleic acid macromolecule based drug products. Drug Discov Today. 2016;21(3):430–444.
  • Evans RK, Xu Z, Bohannon KE, et al. Evaluation of degradation pathways for plasmid DNA in pharmaceutical formulations via accelerated stability studies. J Pharm Sci. 2000;89(1):76–87.
  • Zhao W, Zhang C, Li B, et al. Lipid polymer hybrid nanomaterials for mRNA delivery. Cell Mol Bioeng. 2018;11(5):397–406.
  • Ball RL, Hajj KA, Vizelman J, et al. Lipid nanoparticle formulations for enhanced co-delivery of siRNA and mRNA. Nano Lett. 2018;18(6):3814–3822.
  • Kaczmarek JC, Patel AK, Kauffman KJ, et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew Chem. 2016;128(44):14012–14016.
  • Lacroix C, Humanes A, Coiffier C, et al. Polylactide-based reactive micelles as a robust platform for mRNA delivery. Pharm Res. 2020;37(2):1–12.
  • Li X, Feng Q, Han Z, et al. Enhancing gene editing efficiency for cells by CRISPR/Cas9 system-loaded multilayered nanoparticles assembled via microfluidics. Chin J Chem Eng. 2021;38:216–220.
  • Vencken S, Foged C, Ramsey JM, et al. Nebulised lipid–polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells. ERJ Open Res. 2019;5(2):1–11.
  • Sivadasan D, Sultan MH, Madkhali O, et al. Polymeric Lipid Hybrid Nanoparticles (PLNs) as emerging drug delivery platform—a comprehensive review of their properties, preparation methods, and therapeutic applications. Pharmaceutics. 2021;13(8):1291.
  • Mukherjee A, Waters AK, Kalyan P, et al. Lipid–polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives. Int J Nanomedicine. 2019;14:1937.
  • De A and Ko Y Tag. A tale of nucleic acid–ionizable lipid nanoparticles: Design and manufacturing technology and advancement. Expert Opin Drug Del. 2022;1–17. DOI: 10.1080/17425247.2023.2153832.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.