清脆的
内吞循环
内体
胞浆
Cas9
跨膜蛋白
细胞生物学
化学
融合蛋白
生物
内吞作用
基因
生物化学
细胞内
细胞
酶
重组DNA
受体
作者
Zhicheng Le,Qi Pan,Zepeng He,Hong Liu,Yi Shi,Lixin Liu,Zhijia Liu,Ping Yuan,Yongming Chen
出处
期刊:ACS central science
[American Chemical Society]
日期:2023-06-08
卷期号:9 (7): 1313-1326
被引量:1
标识
DOI:10.1021/acscentsci.3c00207
摘要
Intracellular delivery of therapeutic biomacromolecules is often challenged by the poor transmembrane and limited endosomal escape. Here, we establish a combinatorial library composed of 150 molecular weight-defined gemini amphiphiles (GAs) to identify the vehicles that facilitate robust cytosolic delivery of proteins in vitro and in vivo. These GAs display similar skeletal structures but differential amphiphilicity by adjusting the length of alkyl tails, type of ionizable cationic heads, and hydrophobicity or hydrophilicity of a spacer. The top candidate is highly efficient in translocating a broad spectrum of proteins with various molecular weights and isoelectric points into the cytosol. Particularly, we notice that the entry mechanism is predominantly mediated via the lipid raft-dependent membrane fusion, bypassing the classical endocytic pathway that limits the cytosolic delivery efficiency of many presently available carriers. Remarkably, the top GA candidate is capable of delivering hard-to-deliver Cas9 ribonucleoprotein in vivo, disrupting KRAS mutation in the tumor-bearing mice to inhibit tumor growth and extend their survival. Our study reveals a GA-based small-molecule carrier platform for the direct cytosolic delivery of various types of proteins for therapeutic purposes.
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