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

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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

DOI 10.1038/s41563-020-00886-0PMC PMC8188687

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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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Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
RNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210
Membrane lipids: where they are and how they behave
van Meer, G., Voelker, D. R., & Feigenson, G. W. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2330 · Cited by 7,157
Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing
Cheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J. (2020) · Nature Nanotechnology · doi:10.1038/s41565-020-0669-6 · Cited by 2,383
Self-citation
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822
Delivery materials for siRNA therapeutics
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013) · Nature Materials · doi:10.1038/nmat3765 · Cited by 1,800
Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape
Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681
The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs
Akinc, A., Maier, M. A., Manoharan, M., Fitzgerald, K., Jayaraman, M., Barros, S., Ansell, S., Du, X., Hope, M. J., Madden, T. D., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-019-0591-y · Cited by 1,636
Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo
Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., et al. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203263 · Cited by 1,267

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Background
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Sun, Q., Zhang, H., Ding, F., Gao, X., Zhu, Z., & Yang, C. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.123845 · Cited by 18
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Wu, S., Zhang, Z., Zhao, Z., Cui, C., & Tan, W. (2026) · Chemical Science · doi:10.1039/d5sc06966a · Cited by 21
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Background
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“127 Some NPs also incorporate CPPs or fusogenic peptides on their surface, which interact with the endosomal membrane and promote its destabilization, facilitating the release of the encapsulated cargo into the cytosol.”
Self-citation
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Self-citation
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“[12,26] Similarly, Q. Cheng, T et al. performed an experiment of the SORT in mice based on the charge of the lipid.”
Method
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Xu, Y., Ren, X., Yu, M., Weng, Y., Liu, Y., Song, B., Niu, J., Qiao, Z., Lin, Y., Cao, Y., et al. (2023) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/tb-2023-0802 · Cited by 14
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Background
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The optimization strategies of LNP-mRNA formulations: Development and challenges for further application
Wang, S., Guo, B., Wang, H., & Yang, F. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.105547 · Cited by 14
Translational kinetic‐pharmacodynamics of mRNA‐6231, an investigational mRNA therapeutic encoding mutein interleukin‐2
Rajlic, I. L., Guglieri-López, B., Rangoonwala, N., Ivaturi, V. D., Van, L. M., Mori, S., Wipke, B. T., Burdette, D. S., & Attarwala, H. Z. (2024) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.13142 · Cited by 13
siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice
Ding, Y., Chen, Q., Xu, H., Adi, D., Ding, Y., Luo, W., Zhu, W.-Z., Xu, J.-C., Zhao, X., Shi, X., et al. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100626 · Cited by 14
“Because the bulk of current LNPs target the liver, the challenge of targeted and specific delivery in organs other than the liver must be addressed promptly (43).”
Background
Strategies for Organ‐Targeted mRNA Delivery by Lipid Nanoparticles
Liao, H., Liao, J. P., Zeng, L., Cao, X., Fan, H., & Chen, J. (2024) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.2004 · Cited by 14
Topologically Engineered Supramolecular Cyclolipid Nanoparticles: A Custom-Tailored Delivery System for Inhaled Combination Therapy
Cheng, M., Jiao, Z., Lei, J., Li, M., Yang, K., Qi, S., Yu, X., Wang, Y., Yan, L., & Yu, G. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c03033 · Cited by 14
Self-citation
Nucleic acid vaccines: innovations, efficacy, and applications in at-risk populations
Konopka, E., Edgerton, A. O., & Kutzler, M. A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1584876 · Cited by 14
“Furthermore, inclusion of cholesterol or its derivatives improves LNP stability and endosomal fusion (86), whereas helper lipids in ﬂ uence ﬂ uidity, endosomal fusion (88), and can enable organ speci ﬁ city (89).”
Lipid nanoparticles for mRNA therapy: recent advances in targeted delivery
Wei, T., Tao, W., & Cheng, Q. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac004 · Cited by 15
Self-citation
Formulation and Characterization of Novel Ionizable and Cationic Lipid Nanoparticles for the Delivery of Splice‐Switching Oligonucleotides
Ojansivu, M., Barriga, H. M. G., Holme, M. N., Morf, S., Doutch, J., Andaloussi, S. E., Kjellman, T., Johnsson, M., Barauskas, J., & Stevens, M. M. (2025) · Advanced Materials · doi:10.1002/adma.202419538 · Cited by 13
Recent Advances in mRNA Delivery Systems for Cancer Therapy
Zhang, Z., Fan, Y., Jiang, S., Ma, Y., Yu, Y., Qing, Y., Li, Q., Liu, Y., Shen, S., & Wang, J. (2025) · Advanced Science · doi:10.1002/advs.202417571 · Cited by 17
Intranasal and Pulmonary Lipid Nanoparticles for Gene Delivery: Turning Challenges into Opportunities
Tayyar, Y., Idris, A., & Yassine, H. M. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s517385 · Cited by 12
High-throughput, AI-assisted design and optimization of lipid nanoparticles for drug delivery
Zeng, J., Chen, R., He, S., Zhang, C., Liu, W.-C., Song, H., Liu, S., & Nan, K. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114573 · Cited by 15
Self-citation
Lipid-Based Intelligent Vehicle Capabilitized with Physical and Physiological Activation
Zhang, F., Xia, B., Sun, J., Wang, Y., Wang, J., Xu, F., Chen, J., Lu, M., Yao, X., Timashev, P. S., et al. (2022) · Research · doi:10.34133/2022/9808429 · Cited by 12
“More importantly, this SORT-LNP can be extended to a variety of extra-hepatic organs and tissues, enabling mRNA delivery to lung, kidney, spleen, and even epithelial cells and immune cells.”
BackgroundInfluential
Messenger RNA Therapy for Female Reproductive Health
VanKeulen‐Miller, R., & Fenton, O. S. (2024) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.3c00803 · Cited by 13
Instability of membranes containing ionizable cationic lipids: Effects of the repulsive range of headgroups and tail structures
Huang, H.-C., Lin, C., Sheng, Y., & Tsao, H. (2024) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2024.113807 · Cited by 12
CAR‐T cell therapeutic avenue for fighting cardiac fibrosis: Roadblocks and perspectives
Abdalla, A. M. E., Yu, M., Ahmed, A. I. M., Meng, N., & Ouyang, C. (2024) · Cell Biochemistry and Function · doi:10.1002/cbf.3955 · Cited by 16
“147 However, LNP ‐ mRNA formulations may require different features as vaccines 148,149 4E, which may affect oxygen and nutrient exchange in the heart.”
Background
VitroJet: new features and case studies
Henderikx, R., Mann, D., Domanska, A., Dong, J., Shahzad, S., Lak, B., Filopoulou, A., Ludig, D. L., Grininger, M., Momoh, J., et al. (2024) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s2059798324001852 · Cited by 12
An Amphiphilic Cell‐Penetrating Macrocycle for Efficient Cytosolic Delivery of Proteins, DNA, and CRISPR Cas9
Qutub, S., Bhat, I. A., Maatouk, B. I., Moosa, B., Fakim, A., Nawaz, K., Díaz‐Galicia, E., Lin, W., Grünberg, R., Arold, S. T., et al. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202403647 · Cited by 12
Multicomponent thiolactone-based ionizable lipid screening platform for efficient and tunable mRNA delivery to the lungs
Peña, Á., Heredero, J., Blandín, B., Mata, E., de Miguel, D., Toro-Córdova, A., Alejo, T., Casabona, D., López, A., Gallego-Lleyda, A., et al. (2025) · Communications Chemistry · doi:10.1038/s42004-025-01516-z · Cited by 15
“Thissuggestsapotentialenhanced endosomalescapemechanismofCP-LC-0729LNPsatacidicpH,while maintaininghemocompatibilityatphysiologicalconditions,aresultthat isinaccordancewiththefactthatlipidCP-LC-0729showsahigher invivoperformancethanMC3whiledisplayingnosignsoftoxicity 38 .”
Incorporation of disulfide bonds into ionizable lipids enables efficient splenic mRNA delivery and potent immunotherapy in mice
Li, Y., Cao, Y., Bai, H., Zhang, L., Chen, B., Wu, C., Shuai, Q., & Yan, Y. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.164285 · Cited by 12
Investigating the functional contributions of phospholipids in selective organ targeting lipid nanoparticles
Guerrero, E. D., Vaidya, A., Santelli, J., Tian, Z., Pazzi, G. A., & Siegwart, D. J. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123671 · Cited by 11
Self-citation
Spatial Conformation of Ionizable Lipids Regulates Endosomal Membrane Disruption
Zhao, Y., Qu, Z., Paloncýová, M., Wang, Z., Weng, B., Zhao, Y., Liu, L., Song, D., Wich, D., Otyepka, M., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c10908 · Cited by 13
High-Throughput Screening of Polymer Library for mRNA Tumor Vaccine Carriers with Innate Adjuvant Properties
Tu, Z., Yu, Q., Wu, R., Meng, M., Guo, X., Chen, J., Tang, Z., Hao, K., Tian, H., & Chen, X. (2024) · Chemistry of Materials · doi:10.1021/acs.chemmater.3c03219 · Cited by 11
Lipid Nanoparticles for mRNA Delivery in Cancer Immunotherapy
Alshehry, Y., Liu, X., Li, W., Wang, Q., Cole, J., & Zhu, G. (2025) · The AAPS Journal · doi:10.1208/s12248-025-01051-8 · Cited by 13
“The nature of the lipid tails can also impact the escape of LNPs from endosome (87, 145, 146).”
In vivo demonstration of enhanced mRNA delivery by cyclic disulfide-containing lipid nanoparticles for facilitating endosomal escape
Kimura, S., Okada, K., Matsubara, N., Lyu, F., Tsutsumi, S., Kimura, Y., Hashiya, F., Inagaki, M., Abe, N., & Abe, H. (2025) · RSC Medicinal Chemistry · doi:10.1039/d5md00084j · Cited by 15
Biomembrane-inspired lipid nanoparticles enhance CRISPR-Cas9 editing for hemophilia A
Zhao, J.-J., Tian, S.-N., Peng, Z.-Y., Ren, J., Zhang, Y., Li, G., Deng, D.-H., Zhang, J., & Zhang, X. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114141 · Cited by 11
The engineering challenges and opportunities when designing potent ionizable materials for the delivery of ribonucleic acids
Lau, Y. M. A., Pang, J., Tilstra, G., Couture‐Senécal, J., & Khan, O. F. (2022) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2022.2144827 · Cited by 11
Single-component lipid nanoparticles for engineering SOCS1 gene-silenced dendritic cells to boost tumor immunotherapy
Yu, Z., Wu, M., Huang, Y., Wang, Y., Chen, Y., Long, Q., Lin, Z., Xue, L., Ju, C., & Zhang, C. (2022) · Biomaterials Science · doi:10.1039/d2bm01549h · Cited by 11
Applications and challenges of biomaterial mediated mRNA delivery
Fang, H., & Chen, Q. (2022) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2022.00093 · Cited by 12
Hydatidiform mole: a vascular congenital anomaly.
Reynolds, S. R. M. (1976) · PubMed · Cited by 11
Emerging trends in gene and cell therapy: CRISPR in DNA editing and beyond
Ji, R., Chen, Q., & Zhang, Y. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102459 · Cited by 14
The mRNA-Based Innovative Strategy: Progress and Challenges
Zhou, H., Wei, D., Chen, Z., Chen, H., Dong, C., Cai, W., Wang, J., Liu, X., Li, Y., Yang, Y., et al. (2026) · Nano-Micro Letters · doi:10.1007/s40820-025-01906-x · Cited by 17
Crosslinked ionizable lipids reprogram dendritic cell metabolism for potent mRNA vaccination
Kim, D., Gong, N., Alameh, M., Han, E. L., Wang, H., Wang, J., Feng, E., Yoon, I., Murray, A. M., Shi, Q., et al. (2026) · Nature Materials · doi:10.1038/s41563-026-02512-x · Cited by 10

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.
ORCID: Liu, Shuai
Cheng, Qiang
Wei, Tuo
Johnson, Lindsay T.
Farbiak, Lukas
Siegwart, Daniel J.
Venue: Nature Materials
Publisher: Springer Science and Business Media LLC
Published: 2021-02-04
Volume: 20
Issue: 5
Pages: 701-710
ISSN: 1476-1122 (ISSN-L)
1476-4660
DOI: 10.1038/s41563-020-00886-0
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing

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