CES1-Triggered Liver-Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration.
CES1-Triggered Liver-Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration.
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DOI：
10.1002/advs.202300502
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发表时间：
2023-07
期刊：
影响因子：
15.1
通讯作者：
Yu, Chao
中科院分区：
文献类型：
--
作者：
Zhao, Yunfei;Li, Yun;Wang, Fan;Gan, Xuelan;Zheng, Tianye;Chen, Mengyue;Wei, Li;Chen, Jun;Yu, Chao
关键词：
成簇规则间隔短回文重复序列（CRISPR）/Cas9基因组编辑工具的广泛应用受到其两种组分有效递送到特定细胞和胞质内释放的挑战的阻碍。在本文中，报道了一种用于在体外和体内递送Cas9-mRNA/单向导RNA（Cas9-mRNA/sgRNA）的新型共聚物，其使用羧酸酯酶响应性阳离子三元共聚物纳米颗粒靶向前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）用于高脂血症改善。设计合成了一种二甲基双胍衍生物，将其与甲基丙烯酸丙酯形成阳离子嵌段，再与预聚体共聚，得到三元共聚物mPEG-B-P（Met/n-PMA）。该共聚物可以与Cas9-mRNA/sgRNA自组装，表明纳米颗粒形成递送载体的优异潜力。该载体可以响应于肝细胞羧酸酯酶有效地释放RNA用于基因组编辑。结果表明，mPEG-B-P（Met/n-PMA）/Cas9 mRNA/sgRNA纳米颗粒有效地在肝细胞中积累，导致PCSK 9的抑制，并使小鼠血清中低密度脂蛋白胆固醇和总胆固醇的水平降低至未处理的20%。有趣的是，纳米颗粒甚至可以在调节血糖和体重方面发挥多种功能。本研究建立了一种实现复杂CRISPR组件稳定装载、安全输送和定点释放的新方法，拓展了CRISPR输送系统的应用。这项工作报告了一种新型的基于三元共聚物的递送载体，用于递送Cas9-mRNA和sgPCSK 9，用于体外和体内的基因编辑。在载体中引入羧酸酯酶响应基序，赋予递送载体在肝细胞中的酶响应性，并破坏靶向PCSK 9基因，从而实现对高脂血症的有效治疗效果。
The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9‐mRNA/ single‐guide RNA (Cas9‐mRNA/sgRNA) in vitro and vivo, using carboxylesterase‐responsive cationic triadic copolymeric nanoparticles targeted proprotein convertase subtilisin/kexin type 9 (PCSK9) for hyperlipidemia amelioration is reported. A dimethyl biguanide derivative is designed and synthesized to form cationic block, and copolymerization onto prepolymer with propyl methacrylate, to fabricate a triadic copolymer mPEG‐b‐P(Met/n‐PMA). The copolymer can self‐assemble with Cas9‐mRNA/sgRNA, indicating the excellent potential of nanoparticles to form a delivery carrier. This vehicle can efficiently release RNA in response to the hepatocytes carboxylesterase for genome editing. It was demonstrated that the mPEG‐b‐P(Met/n‐PMA)/Cas9 mRNA/sgRNA nanoparticles effectively accumulated in hepatocytes, lead to the inhibition of PCSK9, and lowered the levels of Low‐density lipoprotein cholesterol and total cholesterol in mouse serum down 20% of nontreatment. Interestingly, the nanoparticles even enable multiple functions in the regulation of blood glucose and weight. This study establishes a novel method to achieve complex CRISPR components stable loading, safe delivery, and fixed‐point release, which expand the application of CRISPR delivery systems. This work reports a novel triadic copolymer‐based delivery vehicle to deliver Cas9‐mRNA and sgPCSK9 for gene editing both in vitro and vivo. Carboxylesterase‐responsive motifs are introduced in the vehicle, endowing the delivery vehicle enzymatic responsiveness in hepatocyte and disrupt the target PCSK9 gene and achieve a potent therapeutic efficacy for hyperlipidemia.
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影响因子：
2.8
作者：
Ferreira, Patrick;Choupina, Altino Branco
通讯作者：
Choupina, Altino Branco
DOI：
10.1002/anie.202010099
发表时间：
2021-01-11
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Rifaie-Graham O;Galensowske NFB;Dean C;Pollard J;Balog S;Gouveia MG;Chami M;Vian A;Amstad E;Lattuada M;Bruns N
通讯作者：
Bruns N
影响因子：
10
作者：
Wang, Hebin;Li, Yang;Ping, Yuan
通讯作者：
Ping, Yuan
DOI：
10.1016/j.jconrel.2021.08.061
发表时间：
2021-10-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Ren J;Cao Y;Li L;Wang X;Lu H;Yang J;Wang S
通讯作者：
Wang S
影响因子：
6.1
作者：
Gabriele, Morena;Puccini, Paola;Longo, Vincenzo
通讯作者：
Longo, Vincenzo