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

Ruan, W; Xu, S; An, Y; Cui, Y; Liu, Y; Wang, Y; Ismail, M; Liu, Y; Zheng, M

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

Ruan, W Xu, S An, Y Cui, Y Liu, Y

Wang, Y Ismail, M Liu, Y

Zheng, M

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: Adv Sci (Weinh), 2024, 11, (33), pp. e2402178
Issue Date:: 2024-09

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Field	Value	Language
dc.contributor.author	Ruan, W
dc.contributor.author	Xu, S
dc.contributor.author	An, Y
dc.contributor.author	Cui, Y
dc.contributor.author	Liu, Y https://orcid.org/0000-0002-8752-4346
dc.contributor.author	Wang, Y
dc.contributor.author	Ismail, M
dc.contributor.author	Liu, Y https://orcid.org/0000-0002-8752-4346
dc.contributor.author	Zheng, M
dc.date.accessioned	2025-04-03T22:00:18Z
dc.date.available	2025-04-03T22:00:18Z
dc.date.issued	2024-09
dc.identifier.citation	Adv Sci (Weinh), 2024, 11, (33), pp. e2402178
dc.identifier.issn	2198-3844
dc.identifier.issn	2198-3844
dc.identifier.uri	http://hdl.handle.net/10453/186573
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	Adv Sci (Weinh)
dc.relation.isbasedon	10.1002/advs.202402178
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Nanocapsules
dc.subject.mesh	Gene Editing
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	CRISPR-Cas Systems
dc.subject.mesh	Humans
dc.subject.mesh	Polo-Like Kinase 1
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Protein Serine-Threonine Kinases
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	ErbB Receptors
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Mice, Nude
dc.subject.mesh	CRISPR-Associated Proteins
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Endodeoxyribonucleases
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Endodeoxyribonucleases
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	Nanocapsules
dc.subject.mesh	CRISPR-Cas Systems
dc.subject.mesh	CRISPR-Associated Proteins
dc.subject.mesh	ErbB Receptors
dc.subject.mesh	Gene Editing
dc.subject.mesh	Protein Serine-Threonine Kinases
dc.subject.mesh	Polo-Like Kinase 1
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Nanocapsules
dc.subject.mesh	Gene Editing
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	CRISPR-Cas Systems
dc.subject.mesh	Humans
dc.subject.mesh	Polo-Like Kinase 1
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Protein Serine-Threonine Kinases
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	ErbB Receptors
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Mice, Nude
dc.subject.mesh	CRISPR-Associated Proteins
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Endodeoxyribonucleases
dc.title	Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.
dc.type	Journal Article
utslib.citation.volume	11
utslib.location.activity	Germany
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-04-03T22:00:14Z
pubs.issue	33
pubs.publication-status	Published
pubs.volume	11
utslib.citation.issue	33

Abstract:

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.

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http://hdl.handle.net/10453/186573