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

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 c...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2022-04, Vol.8 (16), p.eabm8011
Main Authors: Zou, Yan, Sun, Xinhong, Yang, Qingshan, Zheng, Meng, Shimoni, Olga, Ruan, Weimin, Wang, Yibin, Zhang, Dongya, Yin, Jinlong, Huang, Xiangang, Tao, Wei, Park, Jong Bae, Liang, Xing-Jie, Leong, Kam W, Shi, Bingyang
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Blood-Brain Barrier
CRISPR-Cas Systems
Gene Editing
Genetic Therapy
Genetics
Glioblastoma - genetics
Glioblastoma - therapy
Life Sciences
Mice
Nanocapsules
RNA, Guide, CRISPR-Cas Systems - genetics
SciAdv r-articles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abm8011