Henan University Shi Bingyang's team developed a new type of nanocapsules, breaking the blood-brain barrier and efficiently editing brain tumor cells

Written | Edited by Wang Cong | Typesetting by Wang Duoyu | Shui Chengwen CRISPR-Cas9 gene editing technology is considered to be one of the most important breakthroughs in the field of biotechnology since the 21st century, and won the Nobel Prize in Chemistry in 2020
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CRISPR-Cas9-based gene editing enables fast, efficient and precise gene editing at the cellular level and in vivo, bringing unprecedented powerful tools for the treatment of genetic diseases, cancer and other major diseases
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Jennifer Doudna, the founder of CRISPR technology and a Nobel Prize winner, has said that delivery may be the biggest bottleneck in somatic gene editing therapy
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Therefore, the development of a safe and effective CRISPR delivery system is essential for the realization of gene editing in vivo therapy
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In June 2021, Intellia Therapeutics, a company founded by Jennifer Doudna, developed an in vivo CRISPR gene editing therapy delivered by lipid nanoparticles (LNP) for the treatment of transthyretin amyloidosis (ATTR).
Published in the medical journal The New England Journal of Medicine (NEJM)
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These are the first published clinical trial results of an in vivo CRISPR gene-editing therapy, hailed as ushering in a new era of medicine
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However, for brain-related diseases, such as Alzheimer's disease, glioma, etc.
, drug delivery is difficult due to the existence of the blood-brain barrier (BBB), which greatly limits the research progress
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Recently, Prof.
Shi Bingyang and Prof.
Zheng Meng from the Henan University-Macquarie University Biomedical Joint Innovation Center from the School of Life Sciences, Henan University, as co-corresponding authors, published a paper entitled: Blood-brain barrier–penetrating in Science Advances, a sub-journal of Science Research paper on single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy
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This study developed a novel nanocapsule that can safely and effectively deliver CRISPR-Cas9 to the brain non-invasively and target glioma cells, efficiently edit the glioma-related oncogene PLK1 (editing efficiency as high as 38.
1%), and significantly Prolonged survival of glioma mice
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The delivery system developed in this study is able to cross the blood-brain barrier to safely and specifically deliver the CRISPR-Cas9 system into brain tumors, thereby improving the treatment of glioblastoma
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The delivery system is also expected to be used in the treatment of other brain diseases
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This study targets refractory, relapse-prone glioblastoma (GBM), and hopes to develop a novel CRISPR-Cas9 brain delivery platform that meets the following criteria: easy preparation, high loading, small and uniform size, long-term circulation stability , blood-brain barrier permeability, active targeting of the brain and brain tumors, rapid intracellular release, efficient gene editing, and negligible off-targeting,
etc.

The research team modified Angiopep-2, a ligand capable of binding LRP-1 protein, on a thin, disulfide-crosslinked PEG polymer shell, which is found in blood-brain barrier endothelial cells and glue.
High expression on plasmoblastoma
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This modified polymer shell can encapsulate the Cas9-sgRNA ribonucleoprotein complex into small nanocapsules (approximately 30 nm in diameter) with near-neutral surface charges to protect the internal therapeutic components from ribonucleases.
degradation, promoting its blood stability and circulatory life, thereby enhancing its blood-brain barrier permeability
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Next, the research team validated the CRISPR-Cas9 brain-delivery nanocapsules, which transported CRISPR-Cas9 across the blood-brain barrier to target brain diseased cells, effectively editing the oncogene PLK1, and the editing efficiency was as high as 38.
1%.
Reduces PLK1 expression and inhibits division in glioblastoma
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In contrast, off-target gene editing in high-risk tissues (liver, kidney, and normal brain) was negligible (less than 0.
5%)
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More importantly, the median survival time of tumor-bearing mice was significantly prolonged by nearly 3-fold after nanocapsule treatment (24 days vs 68 days)
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Overall, the nanocapsule delivery system developed in this study is able to cross the blood-brain barrier to safely and specifically deliver the CRISPR-Cas9 system into brain tumors, thereby improving the treatment of glioblastoma
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The delivery system is also expected to be used in the treatment of other brain diseases
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It is reported that the research lasted 4 years.
Associate Professor Zou Yan of Henan University and Sun Xinhong, a master student, are the co-first authors of the paper, and Professor Bing Yang and Professor Zheng Meng are the co-corresponding authors.
Strong support from Professor Liang Xingjie, Professor Jong Bea Park of Korea National Cancer Center, Professor Tao Wei of Harvard Medical School and other collaborators
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Paper link: https:// Open for reprinting, welcome to forward to Moments and WeChat groups