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

Zou, Y; Sun, X; Yang, Q; Zheng, M; Shimoni, O; Ruan, W; Wang, Y; Zhang, D; Yin, J; Huang, X; Tao, W; Park, JB; Liang, X-J; Leong, KW; Shi, B

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

Zou, Y Sun, X Yang, Q Zheng, M Shimoni, O

Ruan, W Wang, Y Zhang, D Yin, J Huang, X Tao, W Park, JB Liang, X-J Leong, KW Shi, B

Permalink

Publisher:: AMER ASSOC ADVANCEMENT SCIENCE
Publication Type:: Journal Article
Citation:: Sci Adv, 2022, 8, (16), pp. eabm8011
Issue Date:: 2022-04-22

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download full textAdobe PDF (13.43 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Zou, Y
dc.contributor.author	Sun, X
dc.contributor.author	Yang, Q
dc.contributor.author	Zheng, M
dc.contributor.author	Shimoni, O https://orcid.org/0000-0001-8822-1024
dc.contributor.author	Ruan, W
dc.contributor.author	Wang, Y
dc.contributor.author	Zhang, D
dc.contributor.author	Yin, J
dc.contributor.author	Huang, X
dc.contributor.author	Tao, W
dc.contributor.author	Park, JB
dc.contributor.author	Liang, X-J
dc.contributor.author	Leong, KW
dc.contributor.author	Shi, B
dc.date.accessioned	2023-02-23T00:17:11Z
dc.date.available	2023-02-23T00:17:11Z
dc.date.issued	2022-04-22
dc.identifier.citation	Sci Adv, 2022, 8, (16), pp. eabm8011
dc.identifier.issn	2375-2548
dc.identifier.issn	2375-2548
dc.identifier.uri	http://hdl.handle.net/10453/166342
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER ASSOC ADVANCEMENT SCIENCE
dc.relation	http://purl.org/au-research/grants/arc/IH150100028
dc.relation	http://purl.org/au-research/grants/nhmrc/1101258
dc.relation.ispartof	Sci Adv
dc.relation.isbasedon	10.1126/sciadv.abm8011
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	CRISPR-Cas Systems
dc.subject.mesh	Gene Editing
dc.subject.mesh	Genetic Therapy
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Mice
dc.subject.mesh	Nanocapsules
dc.subject.mesh	RNA, Guide, Kinetoplastida
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Nanocapsules
dc.subject.mesh	Genetic Therapy
dc.subject.mesh	CRISPR-Cas Systems
dc.subject.mesh	Gene Editing
dc.subject.mesh	RNA, Guide, Kinetoplastida
dc.title	Blood-brain barrier-penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy.
dc.type	Journal Article
utslib.citation.volume	8
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - IBMD - Initiative for Biomedical Devices
utslib.copyright.status	open_access	*
dc.date.updated	2023-02-23T00:17:08Z
pubs.issue	16
pubs.publication-status	Published
pubs.volume	8
utslib.citation.issue	16

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/166342