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

Yan Zou, Xinhong Sun, Qingshan Yang, Meng Zheng*, Olga Shimoni, Weimin Ruan, Yibin Wang, Dongya Zhang, Jinlong Yin, Xiangang Huang, Wei Tao, Jong Bae Park, Xing Jie Liang, Kam W. Leong, Bingyang Shi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Citations (Scopus)
119 Downloads (Pure)

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.

Original languageEnglish
Article numbereabm8011
Pages (from-to)1-14
Number of pages14
JournalScience Advances
Volume8
Issue number16
DOIs
Publication statusPublished - 22 Apr 2022

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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