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Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.

Publication ,  Journal Article
Ruan, W; Xu, S; An, Y; Cui, Y; Liu, Y; Wang, Y; Ismail, M; Liu, Y; Zheng, M
Published in: Adv Sci (Weinh)
September 2024

Gene-editing technology shows great potential in glioblastoma (GBM) therapy. Due to the complexity of GBM pathogenesis, a single gene-editing-based therapy is unlikely to be successful; therefore, a multi-gene knockout strategy is preferred for effective GBM inhibition. Here, a non-invasive, biodegradable brain-targeted CRISPR/Cas12a nanocapsule is used that simultaneously targeted dual oncogenes, EGFR and PLK1, for effective GBM therapy. This cargo nanoencapsulation technology enables the CRISPR/Cas12a system to achieve extended blood half-life, efficient blood-brain barrier (BBB) penetration, active tumor targeting, and selective release. In U87MG cells, the combinatorial gene editing system resulted in 61% and 33% knockout of EGFR and PLK1, respectively. Following systemic administration, the CRISPR/Cas12a system demonstrated promising brain tumor accumulation that led to extensive EGFR and PLK1 gene editing in both U87MG and patient-derived GSC xenograft mouse models with negligible off-target gene editing detected through NGS. Additionally, CRISPR/Cas12a nanocapsules that concurrently targeted the EGFR and PLK1 oncogenes showed superior tumor growth suppression and significantly improved the median survival time relative to nanocapsules containing single oncogene knockouts, signifying the potency of the multi-oncogene targeting strategy. The findings indicate that utilization of the CRISPR/Cas12a combinatorial gene editing technique presents a practical option for gene therapy in GBM.

Duke Scholars

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Published In

Adv Sci (Weinh)

DOI

EISSN

2198-3844

Publication Date

September 2024

Volume

11

Issue

33

Start / End Page

e2402178

Location

Germany

Related Subject Headings

  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Polo-Like Kinase 1
  • Nanocapsules
  • Mice, Nude
  • Mice
  • Humans
  • Glioblastoma
  • Gene Editing
  • ErbB Receptors
 

Citation

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Ruan, W., Xu, S., An, Y., Cui, Y., Liu, Y., Wang, Y., … Zheng, M. (2024). Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma. Adv Sci (Weinh), 11(33), e2402178. https://doi.org/10.1002/advs.202402178
Ruan, Weimin, Sen Xu, Yang An, Yingxue Cui, Yang Liu, Yibin Wang, Muhammad Ismail, Yong Liu, and Meng Zheng. “Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.Adv Sci (Weinh) 11, no. 33 (September 2024): e2402178. https://doi.org/10.1002/advs.202402178.
Ruan, Weimin, et al. “Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.Adv Sci (Weinh), vol. 11, no. 33, Sept. 2024, p. e2402178. Pubmed, doi:10.1002/advs.202402178.
Ruan W, Xu S, An Y, Cui Y, Liu Y, Wang Y, Ismail M, Zheng M. Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma. Adv Sci (Weinh). 2024 Sep;11(33):e2402178.
Journal cover image

Published In

Adv Sci (Weinh)

DOI

EISSN

2198-3844

Publication Date

September 2024

Volume

11

Issue

33

Start / End Page

e2402178

Location

Germany

Related Subject Headings

  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Polo-Like Kinase 1
  • Nanocapsules
  • Mice, Nude
  • Mice
  • Humans
  • Glioblastoma
  • Gene Editing
  • ErbB Receptors