Non‐Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co‐Delivery of Cas9 mRNA and sgRNA
Open accessAbstract
CRISPR/Cas is a revolutionary gene editing technology with wide‐ranging utility. The safe, non‐viral delivery of CRISPR/Cas components would greatly improve future therapeutic utility. We report the synthesis and development of zwitterionic amino lipids (ZALs) that are uniquely able to (co)deliver long RNAs including Cas9 mRNA and sgRNAs. ZAL nanoparticle (ZNP) delivery of low sgRNA doses (15 n m ) reduces protein expression by >90 % in cells. In contrast to transient therapies (such as RNAi), we show that ZNP delivery of sgRNA enables permanent DNA editing with an indefinitely sustained 95 % decrease in protein expression. ZNP delivery of mRNA results in high protein expression at low doses in vitro (<600 pM) and in vivo (1 mg kg −1 ). Intravenous co‐delivery of Cas9 mRNA and sgLoxP induced expression of floxed tdTomato in the liver, kidneys, and lungs of engineered mice. ZNPs provide a chemical guide for rational design of long RNA carriers, and represent a promising step towards improving the safety and utility of gene editing.
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Lipid-mediated nanoparticle delivery has been used to transport CRISPR-Cas components in the form of either mRNA/sgRNA or preassembled RNPs into tissues.
“For example, lipid-mediated nanoparticle (LNP) delivery has been used to transport CRISPR-Cas components in the form of either mRNA/sgRNA or preassembled RNPs into tissues 71-74 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [71]
With i.v. injection of ZAL nanoparticles containing Cas9 mRNA and sgRNA, stop gene sequences in Rosa26tdTomato mice were edited, leading to strong tdTO fluorescent signal in the liver, lungs and kidneys.
“With i.v. injection of ZAL nanoparticles containing Cas9 mRNA and sgRNA, the stop gene sequences in Rosa26tdTomato mice were edited, leading to strong tdTO fluorescent signal in the liver, lungs and kidneys.[214]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [214]
Miller et al.'s zwitterionic amino lipid vector showed permanent editing of LoxP gene in genetically engineered mice after intravenous administration.
“In another study, Miller et al. reported a non-viral vector based on zwitterionic amino lipids to deliver Cas9 mRNA and sgRNAs. In contrast to transient therapies, they showed permanent editing of LoxP gene in genetically engineered mice containing a homozygous Rosa26 promoter Lox-Stop-Lox tdTomato (tdTO) cassette after intravenous administration [105].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [105]
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A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116 · see citing works
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 · see citing works
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
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 · see citing works
CRISPR-Cas systems for editing, regulating and targeting genomes
Sander, J. D., & Joung, J. K. (2014) · Nature Biotechnology · doi:10.1038/nbt.2842 · Cited by 3,153 · see citing works
CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling
Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.014 · Cited by 2,001 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Zuris, J. A., Thompson, D. B., Shu, Y., Guilinger, J. P., Bessen, J. L., Hu, J. H., Maeder, M. L., Joung, J. K., Chen, Z.-Y., & Liu, D. R. (2015) · Nature Biotechnology · doi:10.1038/nbt.3081 · Cited by 1,460 · see citing works
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 · see citing works
A combinatorial library of lipid-like materials for delivery of RNAi therapeutics
Akinc, A., Zumbuehl, A., Goldberg, M. S., Leshchiner, E. S., Busini, V., Hossain, N., Bacallado, S., Nguyen, D. N., Fuller, J. E., Alvarez, R., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1402 · Cited by 1,228 · see citing works
In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy
Nelson, C. E., Hakim, C. H., Ousterout, D. G., Thakore, P. I., Moreb, E. A., Rivera, R. M. C., Madhavan, S., Pan, X., Ran, F. A., Yan, W. X., et al. (2016) · Science · doi:10.1126/science.aad5143 · Cited by 1,144 · see citing works
In vivo gene editing in dystrophic mouse muscle and muscle stem cells
Tabebordbar, M., Zhu, K., Cheng, J. K. W., Chew, W. L., Widrick, J. J., Yan, W. X., Maesner, C., Wu, E. Y., Xiao, R., Ran, F. A., et al. (2016) · Science · doi:10.1126/science.aad5177 · Cited by 1,046 · see citing works
Lipid-like materials for low-dose, in vivo gene silencing
Love, K. T., Mahon, K. P., Levins, C. G., Whitehead, K. A., Querbes, W., Dorkin, J. R., Qin, J., Cantley, W., Qin, L. L., Racie, T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910603106 · Cited by 969 · see citing works
Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype
Yin, H., Xue, W., Chen, S., Bogorad, R. L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P. A., Jacks, T., & Anderson, D. G. (2014) · Nature Biotechnology · doi:10.1038/nbt.2884 · Cited by 951 · see citing works
Long, C., Amoasii, L., Mireault, A. A., McAnally, J., Li, H. Z., Sanchez‐Ortiz, E., Bhattacharyya, S., Shelton, J. M., Bassel‐Duby, R., & Olson, E. N. (2015) · Science · doi:10.1126/science.aad5725 · Cited by 941 · see citing works
Genome-wide CRISPR Screen in a Mouse Model of Tumor Growth and Metastasis
Chen, S., Sanjana, N. E., Zheng, K., Shalem, O., Lee, K., Shi, X., Scott, D. A., Song, J. W., Pan, J. Q., Weissleder, R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.02.038 · Cited by 891 · see citing works
Kauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., Fenton, O. S., & Anderson, D. G. (2015) · Nano Letters · doi:10.1021/acs.nanolett.5b02497 · Cited by 785 · see citing works
CRISPR-mediated direct mutation of cancer genes in the mouse liver
Xue, W., Chen, S., Yin, H., Tammela, T., Papagiannakopoulos, T., Joshi, N. S., Cai, W., Yang, G., Bronson, R., Crowley, D. G., et al. (2014) · Nature · doi:10.1038/nature13589 · Cited by 776 · see citing works
Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown
Wittrup, A., Ai, A., Liu, X., Hamar, P., Trifonova, R., Charisse, K., Manoharan, M., Kirchhausen, T., & Lieberman, J. (2015) · Nature Biotechnology · doi:10.1038/nbt.3298 · Cited by 693 · see citing works
Self‐assembled DNA nanoclews for the efficient delivery of CRISPR–Cas9 for genome editing
Sun, W., Ji, W., Hall, J. M., Hu, Q., Wang, C., Beisel, C. L., & Gu, Z. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201506030 · Cited by 629 · see citing works
Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles
Wang, M., Zuris, J. A., Meng, F., Rees, H., Sun, S., Deng, P., Han, Y., Gao, X., Pouli, D., Wu, Q., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520244113 · Cited by 624 · see citing works
A Rapid and General Assay for Monitoring Endogenous Gene Modification
Guschin, D. Y., Waite, A. J., Katibah, G. E., Miller, J. C., Holmes, M. C., & Rebar, E. J. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-753-2_15 · Cited by 500 · see citing works
Self-citationApplications of the CRISPR-Cas9 system in cancer biology
Sánchez-Rivera, F. J., & Jacks, T. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3950 · Cited by 405 · see citing works
Rapid modelling of cooperating genetic events in cancer through somatic genome editing
Rivera, F. J. S., Papagiannakopoulos, T. Y., Romero, R., Tammela, T., Bauer, M. R., Bhutkar, A. J., Joshi, N. S., Subbaraj, L., Bronson, R. T., Xue, W., et al. (2014) · Nature · doi:10.1038/nature13906 · Cited by 404 · see citing works
Polymer–Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs
Kaczmarek, J. C., Patel, A. K., Kauffman, K. J., Fenton, O. S., Webber, M. J., Heartlein, M. W., DeRosa, F., & Anderson, D. G. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201608450 · Cited by 337 · see citing works
Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery
Fenton, O. S., Kauffman, K. J., McClellan, R. L., Appel, E. A., Dorkin, J. R., Tibbitt, M. W., Heartlein, M. W., DeRosa, F., Langer, R., & Anderson, D. G. (2016) · Advanced Materials · doi:10.1002/adma.201505822 · Cited by 254 · see citing works
CRISPR-Cas9 delivery to hard-to-transfect cells via membrane deformation
Han, X., Liu, Z., Jo, M. C., Zhang, K., Li, Y., Zeng, Z., Li, N., Zu, Y., & Qin, L. (2015) · Science Advances · doi:10.1126/sciadv.1500454 · Cited by 232 · see citing works
Zhou, K., Nguyen, L. H., Miller, J. B., Yan, Y., Kós, P., Xiong, H., Li, L., Hao, J., Minnig, J. T., Zhu, H., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520756113 · Cited by 184 · see citing works
Self-citationDesigner lipids for drug delivery: From heads to tails
Kohli, A. G., Kierstead, P. H., Venditto, V. J., Walsh, C. L., & Szoka, F. C. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.04.047 · Cited by 168 · see citing works
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 · doi:10.1002/ange.201203263 · Cited by 150 · see citing works
Self‐Assembled DNA Nanoclews for the Efficient Delivery of CRISPR–Cas9 for Genome Editing
Sun, W., Ji, W., Hall, J. M., Hu, Q., Wang, C., Beisel, C. L., & Gu, Z. (2015) · Angewandte Chemie · doi:10.1002/ange.201506030 · Cited by 131 · see citing works
In Vitro–In Vivo Translation of Lipid Nanoparticles for Hepatocellular siRNA Delivery
Whitehead, K. A., Matthews, J., Chang, P., Niroui, F., Dorkin, J. R., Severgnini, M., & Anderson, D. G. (2012) · ACS Nano · doi:10.1021/nn301922x · Cited by 130 · see citing works
Poly(glycoamidoamine) Brushes Formulated Nanomaterials for Systemic siRNA and mRNA Delivery in Vivo
Dong, Y., Dorkin, J. R., Wang, W., Chang, P., Webber, M. J., Tang, B. C., Yang, J., Ionita, I. A., Danino, D., DeRosa, F., et al. (2016) · Nano Letters · doi:10.1021/acs.nanolett.5b02428 · Cited by 111 · see citing works
Hao, J., Kós, P., Zhou, K., Miller, J. B., Xue, L., Yan, Y., Xiong, H., Elkassih, S. A., & Siegwart, D. J. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b03429 · Cited by 104 · see citing works
Self-citationJarzębińska, A., Pasewald, T., Lambrecht, J., Mykhaylyk, O., Kümmerling, L., Beck, P., Hasenpusch, G., Rudolph, C., Plank, C., & Dohmen, C. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201603648 · Cited by 101 · see citing works
Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells
Yan, Y., Liu, L., Xiong, H., Miller, J. B., Zhou, K., Kós, P., Huffman, K. E., Elkassih, S. A., Norman, J. W., Carstens, R. M., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606886113 · Cited by 88 · see citing works
Self-citationA versatile reporter system for CRISPR-mediated chromosomal rearrangements
Li, Y., Park, A. I., Mou, H., Colpan, C., Bizhanova, A., Akama‐Garren, E. H., Joshi, N., Hendrickson, E. A., Feldser, D. M., Yin, H., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0680-7 · Cited by 64 · see citing works
Polymer–Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs
Kaczmarek, J. C., Patel, A. K., Kauffman, K. J., Fenton, O. S., Webber, M. J., Heartlein, M. W., DeRosa, F., & Anderson, D. G. (2016) · Angewandte Chemie · doi:10.1002/ange.201608450 · Cited by 60 · see citing works
Walsh, C. L., Nguyen, J., & Szoka, F. C. (2012) · Chemical Communications · doi:10.1039/c2cc31710a · Cited by 43 · see citing works
Leung, A. K. K., Hafez, I. M., Baoukina, S., Belliveau, N. M., Zhigaltsev, I. V., Afshinmanesh, E., Tieleman, D. P., Hansen, C. L., Hope, M. J., & Cullis, P. R. (2012) · The Journal of Physical Chemistry C · doi:10.1021/jp3088786 · Cited by 11 · see citing works
Sulfated quaternary amine lipids: a new class of inverse charge zwitterlipids
Venditto, V. J., Dolor, A., Kohli, A. G., Salentinig, S., Boyd, B. J., & Szoka, F. C. (2014) · Chemical Communications · doi:10.1039/c4cc02866j · Cited by 11 · see citing works
Jarzębińska, A., Pasewald, T., Lambrecht, J., Mykhaylyk, O. M., Kümmerling, L., Beck, P., Hasenpusch, G., Rudolph, C., Plank, C., & Dohmen, C. (2016) · Angewandte Chemie · doi:10.1002/ange.201603648 · Cited by 8 · see citing works
Flagged first, then by citations
1 of the 45 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
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 · see citing works
Self-citationDrug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Applications of Nanotechnology in Plant Growth and Crop Protection: A Review
Shang, Y., Hasan, M. K., Ahammed, G. J., Li, M., Yin, H., & Zhou, J. (2019) · Molecules · doi:10.3390/molecules24142558 · Cited by 1,257 · see citing works
Delivering CRISPR: a review of the challenges and approaches
Lino, C. A., Harper, J. C., Carney, J. P., & Timlin, J. A. (2018) · Drug Delivery · doi:10.1080/10717544.2018.1474964 · Cited by 1,185 · see citing works
Targeted drug delivery strategies for precision medicines
Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N. X., Scaltriti, M., & Heller, D. A. (2021) · Nature Reviews Materials · doi:10.1038/s41578-020-00269-6 · Cited by 1,201 · see citing works
The promise and challenge of therapeutic genome editing
Doudna, J. A. (2020) · Nature · doi:10.1038/s41586-020-1978-5 · Cited by 1,126 · see citing works
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127 · see citing works
Finn, J. D., Smith, A. R., Patel, M. C., Shaw, L., Youniss, M. R., van Heteren, J., Dirstine, T., Ciullo, C., Lescarbeau, R., Seitzer, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.014 · Cited by 878 · see citing works
Advances in Biomaterials for Drug Delivery
Fenton, O. S., Olafson, K. N., Pillai, P. S., Mitchell, M. J., & Langer, R. (2018) · Advanced Materials · doi:10.1002/adma.201705328 · Cited by 869 · see citing works
Vakulskas, C. A., Dever, D. P., Rettig, G. R., Turk, R., Jacobi, A. M., Collingwood, M. A., Bode, N. M., McNeill, M. S., Yan, S., Camarena, J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0137-0 · Cited by 782 · see citing works
Tools for translation: non-viral materials for therapeutic mRNA delivery
Hajj, K. A., & Whitehead, K. A. (2017) · Nature Reviews Materials · doi:10.1038/natrevmats.2017.56 · Cited by 799 · see citing works
mRNA-based therapeutics: powerful and versatile tools to combat diseases
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01007-w · Cited by 800 · see citing works
Dilliard, S. A., & Siegwart, D. J. (2023) · Nature Reviews Materials · doi:10.1038/s41578-022-00529-7 · Cited by 707 · see citing works
Self-citationAdvances in the delivery of RNA therapeutics: from concept to clinical reality
Kaczmarek, J. C., Kowalski, P. S., & Anderson, D. G. (2017) · Genome Medicine · doi:10.1186/s13073-017-0450-0 · Cited by 656 · see citing works
Liu, S., Cheng, Q., Wei, T., Yu, X., Johnson, L. T., Farbiak, L., & Siegwart, D. J. (2021) · Nature Materials · doi:10.1038/s41563-020-00886-0 · Cited by 653 · see citing works
Self-citationLipids and Lipid Derivatives for RNA Delivery
Zhang, Y., Sun, C., Wang, C., Jankovic, K. E., & Dong, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00244 · Cited by 638 · see citing works
Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N., & Siegwart, D. J. (2020) · Nature Communications · doi:10.1038/s41467-020-17029-3 · Cited by 603 · see citing works
Self-citationWang, H.-X., Li, M., Lee, C. M., Chakraborty, S., Kim, H.-W., Bao, G., & Leong, K. W. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00799 · Cited by 560 · see citing works
Therapeutic in vivo delivery of gene editing agents
Raguram, A., Banskota, S., & Liu, D. R. (2022) · Cell · doi:10.1016/j.cell.2022.03.045 · Cited by 532 · see citing works
Engineering mesoporous silica nanoparticles for drug delivery: where are we after two decades?
Vallet‐Regí, M., Schüth, F., Lozano, D., Colilla, M., & Manzano, M. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00659b · Cited by 524 · see citing works
Alsaiari, S. K., Patil, S., Alyami, M., Alamoudi, K. O., Aleisa, F. A., Merzaban, J. S., Li, M., & Khashab, N. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.7b11754 · Cited by 517 · see citing works
Qiu, M., Tang, Y., Chen, J., Muriph, R. E., Ye, Z., Huang, C., Evans, J. J., Henske, E. P., & Xu, Q. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2116271119 · Cited by 508 · see citing works
mRNA-based cancer therapeutics
Liu, C., Shi, Q., Huang, X., Koo, S., Kong, N., & Tao, W. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-023-00586-2 · Cited by 500 · see citing works
Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy
Zong, Y., Lin, Y., Wei, T., & Cheng, Q. (2023) · Advanced Materials · doi:10.1002/adma.202303261 · Cited by 495 · see citing works
The challenge and prospect of mRNA therapeutics landscape
Weng, Y., Li, C., Yang, T., Hu, B., Zhang, M., Guo, S., Xiao, H., Liang, X.-J., & Huang, Y. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107534 · Cited by 417 · see citing works
Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities
Li, L., Hu, S., & Chen, X. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.031 · Cited by 415 · see citing works
Wang, P., Zhang, L., Zheng, W., Cong, L., Guo, Z., Xie, Y., Wang, L., Tang, R., Feng, Q., Hamada, Y., et al. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201708689 · Cited by 410 · see citing works
Qiu, M., Glass, Z., Chen, J., Haas, M., Jin, X., Zhao, X., Rui, X., Ye, Z., Li, Y., Zhang, F., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020401118 · Cited by 419 · see citing works
Brief update on endocytosis of nanomedicines
Patel, S., Kim, J., Herrera‐Barrera, M., Mukherjee, A., Kabanov, A. V., & Sahay, G. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.08.004 · Cited by 402 · see citing works
Nanoparticle Delivery of CRISPR/Cas9 for Genome Editing
Duan, L., Ouyang, K., Xu, X. G., Xu, L., Wen, C., Zhou, X., Qin, Z., Xu, Z., Sun, W., & Liang, Y. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.673286 · Cited by 400 · see citing works
Taşaltın, N., Nnamchi, P. S., & Saud, S. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.87879 · Cited by 430 · see citing works
Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery
Eygeris, Y., Patel, S., Jozić, A., & Sahay, G. (2020) · Nano Letters · doi:10.1021/acs.nanolett.0c01386 · Cited by 382 · see citing works
Liu, J., Chang, J., Jiang, Y., Meng, X., Sun, T., Mao, L., Xu, Q., & Wang, M. (2019) · Advanced Materials · doi:10.1002/adma.201902575 · Cited by 373 · see citing works
Microfluidic technologies and devices for lipid nanoparticle-based RNA delivery
Maeki, M., Uno, S., Niwa, A., Okada, Y., & Tokeshi, M. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.017 · Cited by 349 · see citing works
Lipid-Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Components
Kazemian, P., Yu, S.-Y., Thomson, S. B., Birkenshaw, A., Leavitt, B. R., & Ross, C. J. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00916 · Cited by 345 · see citing works
Nucleic acid delivery for therapeutic applications
Gupta, A., Andresen, J. L., Manan, R. S., & Langer, R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113834 · Cited by 339 · see citing works
Evers, M. J. W., Kulkarni, J. A., van der Meel, R., Cullis, P. R., Vader, P., & Schiffelers, R. M. (2018) · Small Methods · doi:10.1002/smtd.201700375 · Cited by 332 · see citing works
CRISPR/Cas9 for cancer research and therapy
Zhan, T., Rindtorff, N., Betge, J., Ebert, M., & Boutros, M. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.04.001 · Cited by 333 · see citing works
Kong, N., Tao, W., Ling, X., Wang, J., Xiao, Y., Shi, S., Ji, X., Shajii, A., Gan, S. T., Kim, N. Y., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw1565 · Cited by 314 · see citing works
Lipid Nanoparticle Formulations for Enhanced Co-delivery of siRNA and mRNA
Ball, R. L., Hajj, K. A., Vizelman, J., Bajaj, P., & Whitehead, K. A. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b01101 · Cited by 314 · see citing works
Sago, C. D., Lokugamage, M. P., Paunovska, K., Vanover, D. A., Monaco, C. M., Shah, N. N., Gamboa Castro, M., Anderson, S. E., Rudoltz, T. G., Lando, G. N., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811276115 · Cited by 313 · see citing works
Hajj, K. A., Ball, R. L., Deluty, S. B., Singh, S. R., Strelkova, D., Knapp, C. M., & Whitehead, K. A. (2019) · Small · doi:10.1002/smll.201805097 · Cited by 312 · see citing works
DNA hydrogel-based gene editing and drug delivery systems
Mo, F., Jiang, K., Zhao, D. S., Wang, Y., Song, J., & Tan, W. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.018 · Cited by 306 · see citing works
Kenjo, E., Hozumi, H., Makita, Y., Iwabuchi, K. A., Fujimoto, N., Matsumoto, S., Kimura, M., Amano, Y., Ifuku, M., Naoe, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26714-w · Cited by 305 · see citing works
Chen, Z., Liu, F., Chen, Y., Liu, J., Wang, X., Chen, A. T., Deng, G., Zhang, H., Liu, J., Hong, Z., et al. (2017) · Advanced Functional Materials · doi:10.1002/adfm.201703036 · Cited by 297 · see citing works
The delivery challenge: fulfilling the promise of therapeutic genome editing
van Haasteren, J., Li, J., Scheideler, O. J., Murthy, N., & Schaffer, D. V. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0565-5 · Cited by 285 · see citing works
LoPresti, S. T., Arral, M. L., Chaudhary, N., & Whitehead, K. A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.046 · Cited by 286 · see citing works
Wang, H.-X., Song, Z., Lao, Y.-H., Xu, X., Gong, J., Cheng, D., Chakraborty, S., Park, J. S., Li, M., Huang, D., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712963115 · Cited by 277 · see citing works
From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases
Pilkington, E. H., Suys, E. J. A., Trevaskis, N. L., Wheatley, A. K., Zukancic, D., Algarni, A., Al-Wassiti, H. A., Davis, T. P., Pouton, C. W., Kent, S. J., et al. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.06.023 · Cited by 265 · see citing works
Cancer‐Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery
Vaughan, H. J., Green, J. J., & Tzeng, S. Y. (2019) · Advanced Materials · doi:10.1002/adma.201901081 · Cited by 257 · see citing works
Emerging mRNA technologies: delivery strategies and biomedical applications
Xiao, Y., Tang, Z., Huang, X., Chen, W., Zhou, J., Liu, H., Liu, C., Kong, N., & Tao, W. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00617g · Cited by 255 · see citing works
Glioblastoma Therapy: Past, Present and Future
Obrador, E., Moreno-Murciano, P., Oriol‐Caballo, M., López‐Blanch, R., Pineda, B., Gutiérrez-Arroyo, J., Loras, A., Bonet, L. G. G., Martínez‐Cadenas, C., Estrela, J. M., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052529 · Cited by 263 · see citing works
Lin, Y., Wang, Y., Ding, J., Jiang, A., Wang, J., Yu, M., Blake, S., Liu, S., Bieberich, C. J., Farokhzad, O. C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aba9772 · Cited by 253 · see citing works
Genome Editing with mRNA Encoding ZFN, TALEN, and Cas9
Zhang, H., Zhang, Y., & Yin, H. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.01.014 · Cited by 248 · see citing works
Zhang, D., Wang, G., Yu, X., Wei, T., Farbiak, L., Johnson, L. T., Taylor, A. M., Xu, J., Hong, Y., Zhu, H., et al. (2022) · Nature Nanotechnology · doi:10.1038/s41565-022-01122-3 · Cited by 243 · see citing works
Self-citationMcKinlay, C. J., Benner, N. L., Haabeth, O. A. W., Waymouth, R. M., & Wender, P. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805358115 · Cited by 240 · see citing works
In vivo gene delivery mediated by non-viral vectors for cancer therapy
Mohammadinejad, R., Dehshahri, A., Madamsetty, V. S., Zahmatkeshan, M., Tavakol, S., Makvandi, P., Khorsandi, D., Pardakhty, A., Ashrafizadeh, M., Afshar, E. G., et al. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.06.038 · Cited by 238 · see citing works
Zou, Y., Sun, X., Yang, Q., Zheng, M., Shimoni, O., Ruan, W., Wang, Y., Zhang, D., Yin, J., Huang, X., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm8011 · Cited by 227 · see citing works
Álvarez‐Benedicto, E., Farbiak, L., Ramírez, M. M., Wang, X., Johnson, L. T., Mian, O. T., Guerrero, E. D., & Siegwart, D. J. (2021) · Biomaterials Science · doi:10.1039/d1bm01454d · Cited by 227 · see citing works
Self-citationNanomedicines to Deliver mRNA: State of the Art and Future Perspectives
Gómez-Aguado, I., Rodríguez-Castejón, J., Vicente-Pascual, M., Rodríguez‐Gascón, A., Solinís, M. Á., & del Pozo‐Rodríguez, A. (2020) · Nanomaterials · doi:10.3390/nano10020364 · Cited by 224 · see citing works
Macrophage-Specific in Vivo Gene Editing Using Cationic Lipid-Assisted Polymeric Nanoparticles
Luo, Y., Xu, C., Li, H., Cao, Z., Liu, J., Wang, J., Du, X., Yang, X., Gu, Z., & Wang, J. (2018) · ACS Nano · doi:10.1021/acsnano.7b07874 · Cited by 223 · see citing works
Ionizable lipid nanoparticles encapsulating barcoded mRNA for accelerated in vivo delivery screening
Guimarães, P. P. G., Zhang, R., Spektor, R., Tan, M., Chung, A., Billingsley, M. M., El-Mayta, R. D., Riley, R., Wang, L., Wilson, J. M., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.10.028 · Cited by 219 · see citing works
Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., Wei, Y., Zhu, H., & Siegwart, D. J. (2018) · Advanced Materials · doi:10.1002/adma.201805308 · Cited by 221 · see citing works
Self-citationKaczmarek, J. C., Kauffman, K. J., Fenton, O. S., Sadtler, K., Patel, A. K., Heartlein, M. W., DeRosa, F., & Anderson, D. G. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b02917 · Cited by 218 · see citing works
Interactions between Biomolecules and Zwitterionic Moieties: A Review
Erfani, A., Seaberg, J., Aichele, C. P., & Ramsey, J. D. (2020) · Biomacromolecules · doi:10.1021/acs.biomac.0c00497 · Cited by 215 · see citing works
Acharya, A., & Pal, P. K. (2020) · NanoImpact · doi:10.1016/j.impact.2020.100232 · Cited by 215 · see citing works
Wang, P., Zhang, L., Xie, Y., Wang, N., Tang, R., Zheng, W., & Jiang, X. (2017) · Advanced Science · doi:10.1002/advs.201700175 · Cited by 213 · see citing works
Melamed, J. R., Yerneni, S. S., Arral, M. L., LoPresti, S. T., Chaudhary, N., Sehrawat, A., Muramatsu, H., Alameh, M., Pardi, N., Weissman, D., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade1444 · Cited by 215 · see citing works
Paunovska, K., Da Silva Sanchez, A. J., Sago, C. D., Gan, Z., Lokugamage, M. P., Islam, F. Z., Kalathoor, S., Krupczak, B. R., & Dahlman, J. E. (2019) · Advanced Materials · doi:10.1002/adma.201807748 · Cited by 205 · see citing works
(2000) · Advanced Materials for Optics and Electronics · doi:10.1002/1099-0712(200001/02)10:1 · Cited by 225 · see citing works
Strategies for nonviral nanoparticle‐based delivery of CRISPR/Cas9 therapeutics
Chen, F., Alphonse, M., & Liu, Q. (2020) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1609 · Cited by 197 · see citing works
Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
Xu, C., Lu, Z.-D., Luo, Y., Liu, Y., Cao, Z., Shen, S., Li, H., Liu, J., Chen, K., Chen, Z., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06522-5 · Cited by 198 · see citing works
Bhagchandani, S. H., Johnson, J. A., & Irvine, D. J. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.013 · Cited by 193 · see citing works
Liu, Q., Zhao, K., Wang, C., Zhang, Z., Zheng, C., Zhao, Y., Zheng, Y., Liu, C., An, Y., Shi, L., et al. (2018) · Advanced Science · doi:10.1002/advs.201801423 · Cited by 189 · see citing works
Spatiotemporal control of CRISPR/Cas9 gene editing
Zhuo, C., Zhang, J., Lee, J., Jiao, J., Cheng, D., Liu, L., Kim, H., Tao, Y., & Li, M. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00645-w · Cited by 196 · see citing works
Rational designs of in vivo CRISPR-Cas delivery systems
Xu, C., Chen, G., Luo, Y., Zhang, Y., Zhao, G., Lu, Z.-D., Czarna, A., Gu, Z., & Wang, J. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.11.005 · Cited by 185 · see citing works
Xue, L., Gong, N., Shepherd, S. J., Xiong, X., Liao, X., Han, X., Zhao, G., Song, C., Huang, X., Zhang, H., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c02706 · Cited by 189 · see citing works
CRISPR Correction of Duchenne Muscular Dystrophy
Min, Y.-L., Bassel‐Duby, R., & Olson, E. N. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-081117-010451 · Cited by 189 · see citing works
Wei, T., Sun, Y., Cheng, Q., Chatterjee, S., Traylor, Z., Johnson, L. T., Coquelin, M. L., Wang, J., Torres, M. J., Lian, X., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42948-2 · Cited by 184 · see citing works
Self-citationHaris, M., Hussain, T., Mohamed, H. I., Khan, A., Ansarì, M. S., Tauseef, A., Khan, A. A., & Akhtar, N. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.159639 · Cited by 183 · see citing works
Advancements and challenges in developing in vivo CAR T cell therapies for cancer treatment
Bui, T. A., Mei, H., Sang, R., Ortega, D., & Deng, W. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105266 · Cited by 168 · see citing works
Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics
Liu, W., Li, L., Jiang, J., Wu, M., & Lin, P. (2021) · Precision Clinical Medicine · doi:10.1093/pcmedi/pbab014 · Cited by 184 · see citing works
Recent Advances in Lipid Nanoparticles for Delivery of mRNA
Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F. H., Zhang, Z., Li, Y., & Huang, W. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122682 · Cited by 178 · see citing works
Duchenne muscular dystrophy: disease mechanism and therapeutic strategies
Angulski, A. B. B., Hosny, N., Cohen, H., Martin, A. A., Hahn, D., Bauer, J., & Metzger, J. M. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1183101 · Cited by 184 · see citing works
Drug delivery systems for CRISPR-based genome editors
Madigan, V. J., Zhang, F., & Dahlman, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00762-x · Cited by 180 · see citing works
Loughrey, D., & Dahlman, J. E. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00601 · Cited by 173 · see citing works
RNA Nanotechnology-Mediated Cancer Immunotherapy
Lin, Y., Wang, Y., Blake, S., Yu, M., Mei, L., Wang, H., & Shi, J. (2019) · Theranostics · doi:10.7150/thno.35568 · Cited by 173 · see citing works
Nanoscale platforms for messenger RNA delivery
Li, B., Zhang, X., & Dong, Y. (2019) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1530 · Cited by 170 · see citing works
Rui, Y., Wilson, D. R., Tzeng, S. Y., Yamagata, H. M., Sudhakar, D., Conge, M., Berlinicke, C. A., Zack, D. J., Tuesca, A. D., & Green, J. J. (2022) · Science Advances · doi:10.1126/sciadv.abk2855 · Cited by 168 · see citing works
Receptor-Mediated Delivery of CRISPR-Cas9 Endonuclease for Cell-Type-Specific Gene Editing
Rouet, R., Thuma, B. A., Roy, M. D., Lintner, N. G., Rubitski, D. M., Finley, J. E., Wisniewska, H. M., Mendonsa, R., Hirsh, A., de Oñate, L., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b01551 · Cited by 163 · see citing works
Self-citationArtificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy
Witten, J. J., Raji, I. O., Manan, R. S., Beyer, E., Bartlett, S., Tang, Y., Ebadi, M., Lei, J., Nguyen, D., Oladimeji, F. A., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02490-y · Cited by 163 · see citing works
Paunovska, K., Gil, C. J., Lokugamage, M. P., Sago, C. D., Sato, M., Lando, G. N., Gamboa Castro, M., Bryksin, A. V., & Dahlman, J. E. (2018) · ACS Nano · doi:10.1021/acsnano.8b03640 · Cited by 160 · see citing works
Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments
Zhang, H., Leal, J., Soto, M. R., Smyth, H. D. C., & Ghosh, D. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12111042 · Cited by 159 · see citing works
Delivery approaches for CRISPR/Cas9 therapeutics in vivo: advances and challenges
Luther, D. C., Lee, Y. W., Nagaraj, H., Scaletti, F., & Rotello, V. M. (2018) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2018.1517746 · Cited by 156 · see citing works
Han, X., Alu, A., Liu, H., Shi, Y., Wei, X., Cai, L., & Wei, Y. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.01.011 · Cited by 159 · see citing works
Granot-Matok, Y., & Peer, D. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.08.015 · Cited by 154 · see citing works
CRISPR/Cas: Advances, Limitations, and Applications for Precision Cancer Research
Yang, Y., Xu, J., Ge, S., & Lai, L. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.649896 · Cited by 160 · see citing works
Engineered CRISPR-Cas systems for the detection and control of antibiotic-resistant infections
Wu, Y., Battalapalli, D., Hakeem, M. J., Selamneni, V., Zhang, P., Draz, M. S., & Ruan, Z. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-01132-8 · Cited by 152 · see citing works
A Potent Branched-Tail Lipid Nanoparticle Enables Multiplexed mRNA Delivery and Gene Editing In Vivo
Hajj, K. A., Melamed, J. R., Chaudhary, N., Lamson, N. G., Ball, R. L., Yerneni, S. S., & Whitehead, K. A. (2020) · Nano Letters · doi:10.1021/acs.nanolett.0c00596 · Cited by 147 · see citing works
- Authors
- Miller, J. B., Zhang, S., Kos, P., Xiong, H., Zhou, K., Perelman, S. S., Zhu, H., & Siegwart, D. J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- University of Texas Southwestern Medical Center Simmons Comprehensive Cancer Center Department of Biochemistry Dallas TX 75390 USA
- Corresponding author
- Siegwart, Daniel J.
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2016-12-16
- Volume
- 56
- Issue
- 4
- Pages
- 1059-1063
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC5521011
- OpenAlex
- W2560987571
- Cited by
- 540
- References
- 45
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 47 · 2023: 48 · 2022: 66 · 2021: 86 · 2020: 79 · 2019: 59 · 2018: 55 · 2017: 24 · 2016: 1
- FWCI
- 24.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA190525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- CRISPR gene editing, lipid nanoparticles, Cas9 mRNA, single guide RNA, co-delivery, in vivo gene editing, loxP
- MeSH terms
- Gene Editing, RNA, Guide, CRISPR-Cas Systems, Lipids, RNA, Messenger, Molecular Structure, RNA, Guide, Kinetoplastida, Gene Transfer Techniques, Nanoparticles, CRISPR-Cas Systems
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