Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads
| Autor: | Roy van der Meel, Dominik Witzigmann, Jerry Leung, Hiu Man Grisch-Chan, Yuen Yi C. Tam, Pieter R. Cullis, Jayesh A. Kulkarni, Maria M. Darjuan, Josh Zaifman, Beat Thöny |
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| Přispěvatelé: | University of Zurich, Kulkarni, Jayesh A, Precision Medicine |
| Rok vydání: | 2019 |
| Předmět: |
Macromolecular Substances
Phospholipid Nanoparticle Macromolecular Substances/chemistry 610 Medicine & health Lipids/chemistry 02 engineering and technology Polyethylene glycol 010402 general chemistry 01 natural sciences Polyethylene Glycols chemistry.chemical_compound PEG ratio Messenger/chemistry General Materials Science Genetic Therapy/methods RNA Messenger Particle Size RNA Small Interfering Liposome Aqueous solution RNA Small Interfering/chemistry Cryoelectron Microscopy Genetic Therapy Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Lipids 2500 General Materials Science 0104 chemical sciences Polyethylene Glycols/chemistry chemistry 10036 Medical Clinic Colloidal gold Liposomes Biophysics RNA Messenger/chemistry RNA Nanoparticles Nanoparticles/chemistry Small Interfering/chemistry 0210 nano-technology Liposomes/chemistry Macromolecule |
| Zdroj: | Nanoscale, 11(18), 9023-9031. Royal Society of Chemistry |
| ISSN: | 2040-3372 2040-3364 |
| DOI: | 10.1039/c9nr02004g |
| Popis: | The success of Onpattro™ (patisiran) clearly demonstrates the utility of lipid nanoparticle (LNP) systems for enabling gene therapies. These systems are composed of ionizable cationic lipids, phospholipid, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced through rapid-mixing of an ethanolic-lipid solution with an acidic aqueous solution followed by dialysis into neutralizing buffer. A detailed understanding of the mechanism of LNP formation is crucial to improving LNP design. Here we use cryogenic transmission electron microscopy and fluorescence techniques to further demonstrate that LNP are formed through the fusion of precursor, pH-sensitive liposomes into large electron-dense core structures as the pH is neutralized. Next, we show that the fusion process is limited by the accumulation of PEG-lipid on the emerging particle. Finally, we show that the fusion-dependent mechanism of formation also applies to LNP containing macromolecular payloads including mRNA, DNA vectors, and gold nanoparticles. |
| Databáze: | OpenAIRE |
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