Customizable virus-like particles deliver CRISPR-Cas9 ribonucleoprotein for effective ocular neovascular and Huntington's disease gene therapy

被引：7

作者：

Ling, Sikai ^{[1
,2
]}

Zhang, Xue ^{[1
]}

Dai, Yao ^{[1
]}

Jiang, Zhuofan ^{[1
]}

Zhou, Xujiao ^{[3
]}

Lu, Sicong ^{[1
]}

Qian, Xiaoqing ^{[4
]}

Liu, Jianping ^{[5
]}

Selfjord, Niklas ^{[6
]}

Satir, Tugce Munise ^{[7
]}

Lundin, Anders ^{[7
]}

Touza, Julia Liz ^{[7
]}

Firth, Mike ^{[8
]}

Van Zuydam, Natalie ^{[9
]}

Bilican, Bilada ^{[7
]}

Akcakaya, Pinar ^{[6
]}

Hong, Jiaxu ^{[3
,10
]}

Cai, Yujia ^{[1
,11
,12
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai, Peoples R China

[2] BDgene Therapeut, Shanghai, Peoples R China

[3] Fudan Univ, Eye & ENT Hosp, Dept Ophthalmol, State Key Lab Med Neurobiol, Shanghai, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China

[5] Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden

[6] AstraZeneca, Genome Engn, Discovery Sci, BioPharmaceut R&D, Gothenburg, Sweden

[7] AstraZeneca, Translat Genom, Discovery Sci, BioPharmaceut R&D, Gothenburg, Sweden

[8] AstraZeneca, Data Sci & Quantitat Biol, Discovery Sci, BioPharmaceut R&D, Cambridge, England

[9] Astrazeneca, Data Sci & Quantitat Biol, Discovery Sci, BioPharmaceut R&D, Gothenburg, Sweden

[10] Shanghai Engn Res Ctr Synthet Immunol, Shanghai, Peoples R China

[11] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, State Key Lab Med Genom, Shanghai, Peoples R China

[12] Shanghai Key Lab Gene Editing & Cell based Immunot, Shanghai, Peoples R China

来源：

NATURE NANOTECHNOLOGY | 2025年 / 20卷 / 04期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

CAS9; RIBONUCLEOPROTEIN; NANOPARTICLE DELIVERY; IMMUNE-RESPONSES; MESSENGER-RNA; EFFICIENT; PROTEIN; BRAIN; TOOLS; CELLS; MODEL;

D O I：

10.1038/s41565-024-01851-7

中图分类号：

TB3 [工程材料学];

学科分类号：

0805 ; 080502 ;

摘要：

In vivo CRISPR gene editing holds enormous potential for various diseases. Ideally, CRISPR delivery should be cell type-specific and time-restricted for optimal efficacy and safety, but customizable methods are lacking. Here we develop a cell-tropism programmable CRISPR-Cas9 ribonucleoprotein delivery system (RIDE) based on virus-like particles. The efficiency of RIDE was comparable to that of adeno-associated virus and lentiviral vectors and higher than lipid nanoparticles. RIDE could be readily reprogrammed to target dendritic cells, T cells and neurons, and significantly ameliorated the disease symptoms in both ocular neovascular and Huntington's disease models via cell-specific gene editing. In addition, RIDE could efficiently edit the huntingtin gene in patients' induced pluripotent stem cell-derived neurons and was tolerated in non-human primates. This study is expected to facilitate the development of in vivo CRISPR therapeutics.

引用

页码：543 / 553

页数：29

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