Cited by 653RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryDendrimers and Hyperbranched Polymers

Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing

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Liu, Shuai, Cheng, Qiang, Wei, Tuo, Yu, Xueliang, Johnson, Lindsay T., Farbiak, Lukas, Siegwart, Daniel J.·2021·Nature Materials

Abstract

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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Crossref · 10.1038/s41563-020-00886-0

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  • Organ selectivity can be achieved by adjusting the proportions of lipid components.

    “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]

  • The delivery efficacy of mRNA could be improved by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle-mRNA formulations.

    “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]

  • Alteration of the alkyl length of a lipid results in selective accumulation of lipid nanoparticle-mRNA formulations in the liver or spleen.

    “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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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
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
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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