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

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

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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	2023-02-23T00:17:13Z
dc.date.available	2023-02-23T00:17:13Z
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/10453/166343
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	2023-02-23T00:14:42Z
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.

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http://hdl.handle.net/10453/166343