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Enhancement of Gene Editing and Base Editing with Therapeutic Ribonucleoproteins through In Vivo Delivery Based on Absorptive Silica Nanoconstruct
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2022-11-03 , DOI: 10.1002/adhm.202201825
Seongchan Kim 1 , You Kyeong Jeong 2 , Chang Sik Cho 3 , SeokHoon Lee 4 , Chang Ho Sohn 5 , Jeong Hun Kim 3, 6 , Youngdo Jeong 1 , Dong Hyun Jo 7 , Sangsu Bae 2, 4 , Hyojin Lee 1, 8
Affiliation  

Key to the widespread and secure application of genome editing tools is the safe and effective delivery of multiple components of ribonucleoproteins (RNPs) into single cells, which remains a biological barrier to their clinical application. To overcome this issue, a robust RNP delivery platform based on a biocompatible sponge-like silica nanoconstruct (SN) for storing and directly delivering therapeutic RNPs, including Cas9 nuclease RNP (Cas9-RNP) and base editor RNP (BE-RNP) is designed. Compared with commercialized material such as lipid-based methods, up to 50-fold gene deletion and 10-fold base substitution efficiency is obtained with a low off-target efficiency by targeting various cells and genes. In particular, gene correction is successfully induced by SN-based delivery through intravenous injection in an in vivo solid-tumor model and through subretinal injection in mouse eye. Moreover, because of its low toxicity and high biodegradability, SN has negligible effect on cellular function of organs. As the engineered SN can overcome practical challenges associated with therapeutic RNP application, it is strongly expected this platform to be a modular RNPs delivery system, facilitating in vivo gene deletion and editing.

中文翻译:


通过基于吸收二氧化硅纳米构建体的体内递送使用治疗性核糖核蛋白增强基因编辑和碱基编辑



基因组编辑工具广泛和安全应用的关键是将核糖核蛋白 (RNP) 的多个成分安全有效地递送到单个细胞中,这仍然是其临床应用的生物屏障。为了克服这个问题,设计了一种基于生物相容性海绵状二氧化硅纳米构建体 (SN) 的稳健 RNP 递送平台,用于储存和直接递送治疗性 RNP,包括 Cas9 核酸酶 RNP (Cas9-RNP) 和碱基编辑器 RNP (BE-RNP)。与基于脂质的方法等商业化材料相比,通过靶向各种细胞和基因,以较低的脱靶效率获得高达 50 倍的基因缺失和 10 倍的碱基替换效率。特别是,在体内实体瘤模型中通过静脉注射和在小鼠眼中通过视网膜下注射,通过基于 SN 的递送成功诱导基因校正。此外,由于其低毒性和高生物降解性,SN 对器官细胞功能的影响可以忽略不计。由于工程化 SN 可以克服与治疗性 RNP 应用相关的实际挑战,因此强烈建议该平台成为一个模块化的 RNPs 递送系统,促进体内基因的缺失和编辑。
更新日期:2022-11-03
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