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Cited by 227RNA Interference and Gene DeliveryCRISPR and Genetic EngineeringNanoparticle-Based Drug Delivery

Blood-brain barrier–penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy

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Zou, Yan, Sun, Xinhong, Yang, Qingshan, Zheng, Meng, Shimoni, Olga, Ruan, Weimin, Wang, Yibin, Zhang, Dongya +7 more·2022·Science Advances
DOI 10.1126/sciadv.abm8011PMC PMC9020780
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Abstract

We designed a unique nanocapsule for efficient single CRISPR-Cas9 capsuling, noninvasive brain delivery and tumor cell targeting, demonstrating an effective and safe strategy for glioblastoma gene therapy. Our CRISPR-Cas9 nanocapsules can be simply fabricated by encapsulating the single Cas9/sgRNA complex within a glutathione-sensitive polymer shell incorporating a dual-action ligand that facilitates BBB penetration, tumor cell targeting, and Cas9/sgRNA selective release. Our encapsulating nanocapsules evidenced promising glioblastoma tissue targeting that led to high PLK1 gene editing efficiency in a brain tumor (up to 38.1%) with negligible (less than 0.5%) off-target gene editing in high-risk tissues. Treatment with nanocapsules extended median survival time (68 days versus 24 days in nonfunctional sgRNA-treated mice). Our new CRISPR-Cas9 delivery system thus addresses various delivery challenges to demonstrate safe and tumor-specific delivery of gene editing Cas9 ribonucleoprotein for improved glioblastoma treatment that may potentially be therapeutically useful in other brain diseases.

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Authors
Zou, Y., Sun, X., Yang, Q., Zheng, M., Shimoni, O., Ruan, W., Wang, Y., Zhang, D., Yin, J., Huang, X., Tao, W., Park, J. B., Liang, X.-J., Leong, K. W., & Shi, B.
Affiliations
  • Henan University (CN)
  • University of Technology Sydney (AU)
  • Harvard University (US)
  • National Cancer Center (KR)
  • Chinese Academy of Sciences (CN)
  • Columbia University (US)
Corresponding author
  • Zou, Yan
  • Sun, Xinhong
  • Zheng, Meng
  • Shi, Bingyang
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-04-22
Volume
8
Issue
16
Pages
eabm8011-eabm8011
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abm8011
PMC
PMC9020780
OpenAlex
W4224247454
Cited by
227
References
15
Citations by year
2026: 44 · 2025: 64 · 2024: 60 · 2023: 45 · 2022: 14
FWCI
14.94
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
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, glioblastoma, gene therapy, nanocapsules, blood-brain barrier penetration, tumor cell targeting, PLK1, genome editing, off-target effects, brain drug delivery, ribonucleoprotein delivery
MeSH terms
Gene Editing, RNA, Guide, CRISPR-Cas Systems, Animals, Blood-Brain Barrier, Glioblastoma, Genetic Therapy, RNA, Guide, Kinetoplastida, Mice, Nanocapsules, CRISPR-Cas Systems

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