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

doi:10.1002/advs.202402178

科研成果详情

题名	Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma
作者	Ruan, Weimin 1; Xu, Sen 1; An, Yang 2; Cui, Yingxue 1; Liu, Yang 1; Wang, Yibin 1; Ismail, Muhammad 1; Liu, Yong3; Zheng, Meng 1
发表日期	2024-06-28
发表期刊	Advanced Science 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access
关键词	Cas12a CRISPR gene-editing glioblastoma nanocapsule
其他关键词	GENOME ; DELIVERY ; SYSTEM ; CELLS ; SPECIFICITIES
摘要	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. A biodegradable brain-targeted CRISPR/Cas12a nanocapsule (ANC@RNP) simultaneously targeted EGFR and PLK1 for effective GBM therapy. ANC@RNP achieved extended blood half-life, efficient blood-brain barrier (BBB) penetration, active tumor targeting, and selective release. ANC@RNP lead to robust combinatorial gene editing and showed superior tumor growth suppression in U87MG and patient-derived GSC orthotopic xenograft mouse models with negligible off-target gene editing. image
资助项目	National Natural Science Foundation of China (NSFC) [52073079, 52373133, U20A20338]; Henan Natural Science Foundation [K23036Y, 232300421044]; Henan University Double First-Class Foundation; Key Research and Development Program of Zhejiang Province [2021C04019]
出版者	WILEY
ISSN	2198-3844
EISSN	2198-3844
卷号	11 期号:33
DOI	10.1002/advs.202402178
页数	15
WOS类目	Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary
WOS研究方向	Chemistry ; Science & Technology - Other Topics ; Materials Science
WOS记录号	WOS:001257402100001
收录类别	SCIE ; PUBMED ; EI ; SCOPUS
EI入藏号	20242616530555
EI主题词	Nanocapsules
EI分类号	461.2 Biological Materials and Tissue Engineering ; 461.8.1 Genetic Engineering ; 761 Nanotechnology ; 801.2 Biochemistry ; 933 Solid State Physics
URL	查看原文
PubMed ID	38943253
SCOPUSEID	2-s2.0-85197939228
通讯作者地址	[Zheng, Meng]Henan Univ, Henan Macquarie Univ Joint Ctr Biomed Innovat, Henan Key Lab Brain Targeted Bionanomed, Sch Life Sci,Henan Int Joint Lab Nanobiomed, Kaifeng 475004, Henan, Peoples R China. ; [Liu, Yong]Wenzhou Med Univ, Sch Ophthalmol & Optometry, Sch Biomed Engn, 270 Xuanyuanxi Rd, Wenzhou 325027, Zhejiang, Peoples R China.
Scopus学科分类	Medicine (miscellaneous);Chemical Engineering (all);Materials Science (all);Biochemistry, Genetics and Molecular Biology (miscellaneous);Engineering (all);Physics and Astronomy (all)
SCOPUS_ID	SCOPUS_ID:85197939228
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/215236
专题	眼视光学院（生物医学工程学院）、附属眼视光医院眼视光学院（生物医学工程学院）、附属眼视光医院_医学工程系
通讯作者	Liu, Yong; Zheng, Meng
作者单位	1.Henan Univ, Henan Macquarie Univ Joint Ctr Biomed Innovat, Henan Key Lab Brain Targeted Bionanomed, Sch Life Sci,Henan Int Joint Lab Nanobiomed, Kaifeng 475004, Henan, Peoples R China; 2.Henan Univ, Henan Prov Engn Ctr Tumor Mol Med, Sch Basic Med Sci, Kaifeng 475004, Henan, Peoples R China; 3.Wenzhou Med Univ, Sch Ophthalmol & Optometry, Sch Biomed Engn, 270 Xuanyuanxi Rd, Wenzhou 325027, Zhejiang, Peoples R China
通讯作者单位	眼视光学院（生物医学工程学院）、附属眼视光医院; 医学工程系
推荐引用方式 GB/T 7714	Ruan, Weimin,Xu, Sen,An, Yang,et al. Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma[J]. Advanced Science,2024,11(33).
APA	Ruan, Weimin., Xu, Sen., An, Yang., Cui, Yingxue., Liu, Yang., ... & Zheng, Meng. (2024). Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma. Advanced Science, 11(33).
MLA	Ruan, Weimin,et al."Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma".Advanced Science 11.33(2024).