Cited by 277RNA Interference and Gene DeliveryCRISPR and Genetic EngineeringNanoparticle-Based Drug Delivery

Nonviral gene editing via CRISPR/Cas9 delivery by membrane-disruptive and endosomolytic helical polypeptide

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Wang, Hong-Xia, Song, Ziyuan, Lao, Yeh-Hsing, Xu, Xin, Gong, Jing, Cheng, Du, Chakraborty, Syandan, Park, Ji Sun +5 more·2018·Proceedings of the National Academy of Sciences

Abstract

Effective and safe delivery of the CRISPR/Cas9 gene-editing elements remains a challenge. Here we report the development of PEGylated nanoparticles (named P-HNPs) based on the cationic α-helical polypeptide poly(γ-4-((2-(piperidin-1-yl)ethyl)aminomethyl)benzyl-l-glutamate) for the delivery of Cas9 expression plasmid and sgRNA to various cell types and gene-editing scenarios. The cell-penetrating α-helical polypeptide enhanced cellular uptake and promoted escape of pCas9 and/or sgRNA from the endosome and transport into the nucleus. The colloidally stable P-HNPs achieved a Cas9 transfection efficiency up to 60% and sgRNA uptake efficiency of 67.4%, representing an improvement over existing polycation-based gene delivery systems. After performing single or multiplex gene editing with an efficiency up to 47.3% in vitro, we demonstrated that P-HNPs delivering Cas9 plasmid/sgRNA targeting the polo-like kinase 1 (Plk1) gene achieved 35% gene deletion in HeLa tumor tissue to reduce the Plk1 protein level by 66.7%, thereby suppressing the tumor growth by >71% and prolonging the animal survival rate to 60% within 60 days. Capable of delivering Cas9 plasmids to various cell types to achieve multiplex gene knock-out, gene knock-in, and gene activation in vitro and in vivo, the P-HNP system offers a versatile gene-editing platform for biological research and therapeutic applications.

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  • A membrane-penetrating cationic α-helical polypeptide enhanced cellular internalization of Cas9 plasmid and sgRNA.

    “Similarly, Wang et al. synthesized a membrane-penetrating cationic α-helical polypeptide which enhanced cellular internalization of Cas9 plasmid and sgRNA.[228]”

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Authors
Wang, H.-X., Song, Z., Lao, Y.-H., Xu, X., Gong, J., Cheng, D., Chakraborty, S., Park, J. S., Li, M., Huang, D., Yin, L., Cheng, J., & Leong, K. W.
Affiliations
  • Department of Biomedical Engineering, Columbia University, New York, NY 10027;
  • University of Illinois Urbana-Champaign (US)
  • Columbia University (US)
  • Soochow University (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • Yin, Lichen
  • Cheng, Jianjun
  • Leong, Kam W.
Venue
Proceedings of the National Academy of Sciences
Published
2018-04-23
Volume
115
Issue
19
Pages
4903-4908
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2802061036
Cited by
277
References
34
Citations by year
2026: 9 · 2025: 18 · 2024: 21 · 2023: 41 · 2022: 47 · 2021: 41 · 2020: 43 · 2019: 42 · 2018: 15
FWCI
12.54
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Columbia Academic Commons (Columbia University)
Funders
  • National Natural Science Foundation of China (51573123, 51722305)
  • Ministry of Science and Technology of the People's Republic of China (2016YFA0201200)
  • Guangdong Innovative and Entrepreneurial Research Team Program (NO.2013S086)
  • Global Research Laboratory Program Korean NSF (2015032163)
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/Cas9 delivery, PEGylated nanoparticles, cell-penetrating peptides, endosomal escape, multiplex genome editing, PLK1, tumor growth inhibition, gene knock-in, gene activation
MeSH terms
Gene Editing, Animals, HeLa Cells, Humans, Plasmids, Gene Transfer Techniques, K562 Cells, NIH 3T3 Cells, Mice, Nanoparticles, HEK293 Cells, Cell-Penetrating Peptides, CRISPR-Cas Systems

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