Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles
Abstract Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano‐delivery system for therapeutic nucleic acids. The great effort put in the development of ionizable lipids with increased in vivo potency brought LNPs from the laboratory benches to the FDA approval of patisiran in 2...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-05-01
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| Series: | Bioengineering & Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/btm2.10213 |
| _version_ | 1818453689076023296 |
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| author | Michele Schlich Roberto Palomba Gabriella Costabile Shoshy Mizrahy Martina Pannuzzo Dan Peer Paolo Decuzzi |
| author_facet | Michele Schlich Roberto Palomba Gabriella Costabile Shoshy Mizrahy Martina Pannuzzo Dan Peer Paolo Decuzzi |
| author_sort | Michele Schlich |
| collection | DOAJ |
| description | Abstract Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano‐delivery system for therapeutic nucleic acids. The great effort put in the development of ionizable lipids with increased in vivo potency brought LNPs from the laboratory benches to the FDA approval of patisiran in 2018 and the ongoing clinical trials for mRNA‐based vaccines against SARS‐CoV‐2. Despite these success stories, several challenges remain in RNA delivery, including what is known as “endosomal escape.” Reaching the cytosol is mandatory for unleashing the therapeutic activity of RNA molecules, as their accumulation in other intracellular compartments would simply result in efficacy loss. In LNPs, the ability of ionizable lipids to form destabilizing non‐bilayer structures at acidic pH is recognized as the key for endosomal escape and RNA cytosolic delivery. This is motivating a surge in studies aiming at designing novel ionizable lipids with improved biodegradation and safety profiles. In this work, we describe the journey of RNA‐loaded LNPs across multiple intracellular barriers, from the extracellular space to the cytosol. In silico molecular dynamics modeling, in vitro high‐resolution microscopy analyses, and in vivo imaging data are systematically reviewed to distill out the regulating mechanisms underlying the endosomal escape of RNA. Finally, a comparison with strategies employed by enveloped viruses to deliver their genetic material into cells is also presented. The combination of a multidisciplinary analytical toolkit for endosomal escape quantification and a nature‐inspired design could foster the development of future LNPs with improved cytosolic delivery of nucleic acids. |
| first_indexed | 2024-12-14T21:42:58Z |
| format | Article |
| id | doaj.art-59727285d9c041cfa4813bef3b0fc601 |
| institution | Directory Open Access Journal |
| issn | 2380-6761 |
| language | English |
| last_indexed | 2024-12-14T21:42:58Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Bioengineering & Translational Medicine |
| spelling | doaj.art-59727285d9c041cfa4813bef3b0fc6012022-12-21T22:46:25ZengWileyBioengineering & Translational Medicine2380-67612021-05-0162n/an/a10.1002/btm2.10213Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticlesMichele Schlich0Roberto Palomba1Gabriella Costabile2Shoshy Mizrahy3Martina Pannuzzo4Dan Peer5Paolo Decuzzi6Fondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyFondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyFondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyFondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyFondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyLaboratory of Precision NanoMedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv IsraelFondazione Istituto Italiano di Tecnologia Laboratory of Nanotechnology for Precision Medicine Genoa ItalyAbstract Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano‐delivery system for therapeutic nucleic acids. The great effort put in the development of ionizable lipids with increased in vivo potency brought LNPs from the laboratory benches to the FDA approval of patisiran in 2018 and the ongoing clinical trials for mRNA‐based vaccines against SARS‐CoV‐2. Despite these success stories, several challenges remain in RNA delivery, including what is known as “endosomal escape.” Reaching the cytosol is mandatory for unleashing the therapeutic activity of RNA molecules, as their accumulation in other intracellular compartments would simply result in efficacy loss. In LNPs, the ability of ionizable lipids to form destabilizing non‐bilayer structures at acidic pH is recognized as the key for endosomal escape and RNA cytosolic delivery. This is motivating a surge in studies aiming at designing novel ionizable lipids with improved biodegradation and safety profiles. In this work, we describe the journey of RNA‐loaded LNPs across multiple intracellular barriers, from the extracellular space to the cytosol. In silico molecular dynamics modeling, in vitro high‐resolution microscopy analyses, and in vivo imaging data are systematically reviewed to distill out the regulating mechanisms underlying the endosomal escape of RNA. Finally, a comparison with strategies employed by enveloped viruses to deliver their genetic material into cells is also presented. The combination of a multidisciplinary analytical toolkit for endosomal escape quantification and a nature‐inspired design could foster the development of future LNPs with improved cytosolic delivery of nucleic acids.https://doi.org/10.1002/btm2.10213endosomal escapeintracellular deliveryionizable lipidsLNPsmRNARNA delivery |
| spellingShingle | Michele Schlich Roberto Palomba Gabriella Costabile Shoshy Mizrahy Martina Pannuzzo Dan Peer Paolo Decuzzi Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles Bioengineering & Translational Medicine endosomal escape intracellular delivery ionizable lipids LNPs mRNA RNA delivery |
| title | Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles |
| title_full | Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles |
| title_fullStr | Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles |
| title_full_unstemmed | Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles |
| title_short | Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles |
| title_sort | cytosolic delivery of nucleic acids the case of ionizable lipid nanoparticles |
| topic | endosomal escape intracellular delivery ionizable lipids LNPs mRNA RNA delivery |
| url | https://doi.org/10.1002/btm2.10213 |
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