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Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing
Open accessAbstract
Endosomal escape remains a fundamental barrier hindering the advancement of nucleic acid therapeutics. Taking inspiration from natural phospholipids that comprise biological membranes, we report the combinatorial synthesis of multi-tailed ionizable phospholipids (iPhos) capable of delivering messenger RNA or mRNA/single-guide RNA for gene editing in vivo. Optimized iPhos lipids are composed of one pH-switchable zwitterion and three hydrophobic tails, which adopt a cone shape in endosomal acidic environments to facilitate membrane hexagonal transformation and subsequent cargo release from endosomes. Structure-activity relationships reveal that iPhos chemical structure can control in vivo efficacy and organ selectivity. iPhos lipids synergistically function with various helper lipids to formulate multi-component lipid nanoparticles (called iPLNPs) for selective organ targeting. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR-Cas9 gene editing in spleen, liver and lungs (respectively) following intravenous administration. This rational design of functional phospholipids demonstrates substantial value for gene editing research and therapeutic applications.
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“Organ selectivity can also be achieved by adjusting the proportions of lipid components, for example, to design spleen-targeted mRNA vaccines26,27 or lung-targeted genome editing delivery systems114,134.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [114]
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“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [114]
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“For example, alteration of the alkyl length of a lipid results in selective accumulation of lipid nanoparticle–mRNA formulations in the liver or spleen114.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [114]
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Metadata
- Authors
- Liu, S., Cheng, Q., Wei, T., Yu, X., Johnson, L. T., Farbiak, L., & Siegwart, D. J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Siegwart, Daniel J.
- Venue
- Nature Materials
- Published
- 2021-02-04
- Volume
- 20
- Issue
- 5
- Pages
- 701-710
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC8188687
- OpenAlex
- W3127944141
- Cited by
- 653
- References
- 54
- Citations by year
- 2026: 107 · 2025: 154 · 2024: 139 · 2023: 122 · 2022: 90 · 2021: 40
- FWCI
- 30.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP160157)
- U.S. Department of Health & Human Services | National Institutes of Health (R01 EB025192-01A1)
- American Cancer Society (RSG-17-012-01)
- Welch Foundation (I-1855)
- Cystic Fibrosis Foundation (SIEGWA18XX0)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (5P30CA142543)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- endosomal escape, mRNA delivery, CRISPR/Cas9 genome editing, lipid nanoparticles, zwitterionic lipids, membrane perturbation, structure-activity relationship, helper lipids, nucleic acid therapeutics
- MeSH terms
- Gene Editing, Animals, Cell Line, Cell Membrane, Female, Organ Specificity, Phospholipids, RNA, Messenger, Drug Delivery Systems, Mice, Administration, Intravenous, CRISPR-Cas Systems
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