Customizable virus-like particles deliver CRISPR–Cas9 ribonucleoprotein for effective ocular neovascular and Huntington’s disease gene therapy
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.
Authors
- Sicong Lu (ORCID: https://orcid.org/0000-0002-9054-7303)
- Natalie R. van Zuydam (ORCID: https://orcid.org/0000-0002-9809-1398)
- Julia Liz Touza
- Niklas Selfjord (ORCID: https://orcid.org/0009-0008-5628-5849)
- Yujia Cai (ORCID: https://orcid.org/0000-0002-2955-7289)
- Anders Lundin (ORCID: https://orcid.org/0000-0003-3131-8022)
- Sikai Ling
- Bilada Bilican (ORCID: https://orcid.org/0000-0002-3057-2654)
- Jiaxu Hong (ORCID: https://orcid.org/0000-0001-9912-633X)
- Jianping Liu (ORCID: https://orcid.org/0000-0002-7336-3895)
- Mike Firth
- Tuğçe Munise Şatır (ORCID: https://orcid.org/0000-0001-9021-1650)
- Xujiao Zhou (ORCID: https://orcid.org/0000-0002-9719-4889)
- Xue Zhang (ORCID: https://orcid.org/0000-0003-3411-7103)
- Xiaoqing Qian
- Yao Dai
- Zhuofan Jiang
- Pinar Akcakaya (ORCID: https://orcid.org/0000-0001-8413-8995)
Institutions
- AstraZeneca (United Kingdom) (GB)
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Karolinska Institutet (SE)
- Eye & ENT Hospital of Fudan University (CN)
- State Key Laboratory of Synthetic Chemistry (CN)
- AstraZeneca (Sweden) (SE)
- Shanghai Cell Therapy Research Institute (CN)
- Regend Therapeutics (China) (CN)
Publication Details
- Journal
- Nature Nanotechnology
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1038/s41565-024-01851-7
- Citations
- 50
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 40.30
Funders
- AstraZeneca
- CHDI Foundation
- Aarhus Universitet
- University College London
- National Natural Science Foundation of China
- Shanghai Jiao Tong University
- Fundamental Research Funds for the Central Universities
- Overseas Expertise Introduction Center for Discipline Innovation of Food Nutrition and Human Health (111 Center)