Progress in the miniaturization of CRISPR-Cas systems

DONG Ying; MA Mengdan; HUANG Weiren

doi:10.12211/2096-8280.2023-068

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Progress in the miniaturization of CRISPR-Cas systems

Invited Review | 更新时间：2025-06-20

- Progress in the miniaturization of CRISPR-Cas systems
- Synthetic Biology Journal Vol. 6, Issue 1, Pages: 105-117(2025)
- 作者机构：
  
  1.深圳大学第一附属医院泌尿外科，国家地方联合肿瘤基因组临床应用关键技术工程实验室，广东深圳 518036
  2.中国科学院深圳先进技术研究院合成生物学研究所，广东深圳 518000
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2023-068
  CLC： Q816
- Received：21 September 2023，
  
  Revised：2024-03-21，
  
  Published：31 January 2025
- 稿件说明：
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董颖，马孟丹，黄卫人. CRISPR-Cas系统的小型化研究进展［J］. 合成生物学， 2025， 6（1）： 105-117

DONG Ying， MA Mengdan， HUANG Weiren. Progress in the miniaturization of CRISPR-Cas systems［J］. Synthetic Biology Journal， 2025， 6（1）： 105-117
董颖，马孟丹，黄卫人. CRISPR-Cas系统的小型化研究进展［J］. 合成生物学， 2025， 6（1）： 105-117 DOI： 10.12211/2096-8280.2023-068.

DONG Ying， MA Mengdan， HUANG Weiren. Progress in the miniaturization of CRISPR-Cas systems［J］. Synthetic Biology Journal， 2025， 6（1）： 105-117 DOI： 10.12211/2096-8280.2023-068.

摘要

CRISPR-Cas基因编辑技术由于其简便性和高效性，已被广泛应用于生物学、医学、农学等领域的基础与应用研究。目前广泛使用的Cas核酸酶均具有较大的分子量（通常大于1000个氨基酸），而广泛应用于基因治疗中的腺相关病毒（AAV）载体的承载容量却十分有限，在容纳CRISPR核酸酶与gRNA的编码序列之余往往难以承载更多其他功能元件，如碱基编辑、转录调控、多基因编辑等相应元件，这严重限制了其在基因治疗等领域的应用。使用紧凑型Cas蛋白变体的CRISPR-Cas系统可能有助于用AAV产生和传递基因组编辑和调节工具到人类细胞。因此，小型化的CRISPR-Cas系统开发是解决这一技术难题的重要途径，本文主要概括了基于Cas9、Cas12和Cas13蛋白系统在小型化方面的研究进展，包括筛选新型Cas蛋白、缩减蛋白结构域以及引导RNA的改造等，旨在为开发微型精准基因编辑和调控工具提供新思路。目前小型化的CRISPR-Cas系统的局限性主要体现在蛋白分子量的大小和基因编辑的效率、特异性不可兼得上，在未来的研究中若能解决这一问题，获得更小型化的结构域，相信不仅能够优化该系统在体内的传递，更有望为临床带来高效率且低损害的治疗方法。

Abstract

The CRISPR-Cas gene editing technology has revolutionized the fields of biology

medicine

agronomy

etc

. due to its simplicity and efficiency. Laboratory-developed tools

such as the widely recognized CRISPR-

Cas9

have played a pivotal role in addressing a multitude of genetic diseases. By harnessing the targeted nucleic acid capabilities of the CRISPR-Cas system

researchers have successfully integrated various functionalities into Cas proteins

including fluorescent markers

transcriptional regulatory proteins

and base editing components. This has unlocked new possibilities

including chromosome imaging

transcriptional regulation

and precise base editing. Currently

Cas nucleases with large molecular weights

often exceeding 1000 amino acids

are commonly used. However

adeno-associated virus (AAV) vectors

which are extensively employed in gene therapy

have limited capacity to accommodate additional functional components beyond the coding sequences of CRISPR nucleases and guide RNAs (gRNAs). This limitation severely constrains their utilization in gene therapy and other applications. As a result

a significant focus of research has been placed on the miniaturization of CRISPR tools

making them compact enough to align with current delivery methods. Compact Cas protein variants within CRISPR-Cas systems hold the potential to create and deliver genome editing and regulatory tools into human cells using AAV. Hence

the development of miniaturized CRISPR-Cas systems presents a crucial avenue for addressing this technical challenge. This article provides a comprehensive review of research progress in miniaturizing key proteins within two classes of Cas systems: Cas9 and Cas12 for targeting DNA

and Cas13 for targeting RNA. This review encompasses the screening of novel Cas proteins

the reduction of protein structural domains

and the modification of guide RNAs

all with the intention of presenting innovative ideas for the further advancement of compact

precise gene editing

and regulatory tools. The miniaturization of CRISPR-Cas systems is a critical step toward unlocking their full potential in various fields

including biomedicine

agriculture

and basic research. As researchers continue to explore and refine t

hese compact gene editing and regulatory tools

we can expect significant advancement in understanding and manipulating genetic information. This ongoing progress promises to have a profound impact on the future of science and technology. At present

the limitations of the miniaturized CRISPR-Cas system are mainly with the size of protein molecular weight and the efficiency and specificity of gene editing. If we can solve these problems and obtain a smaller structure in future research

not only can we optimize the transmission of the system in the body

but also develop high-efficiency and low-damage treatment methods for clinic applications.

关键词

Keywords

references

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