解读结构决定因素 区分活跃与非活跃的细胞透的细胞核mRNA输送的细胞核mRNA输送
Rik Oude Egberink1, Alexander H van Asbeck1, Milou Boswinkel1
1Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Bioconjugate chemistry
|September 21, 2023
概括
细胞透 (CPP) 对于输送核酸至关重要,但有效的细胞溶液输送仍然具有挑战性. 修改人体乳酸衍生的CPPs以histidines或膜破坏动机等特征改善了交付,突出了核酸交付系统的关键原则.
科学领域:
- 纳米医学是一种纳米医学.
- 生物技术是生物技术.
- 分子生物学分子生物学
背景情况:
- 介质聚合物和阴离子寡核化物 (ONs) 之间的非共价复合体形成是ON传递的关键策略.
- 细胞透 (CPP) 是用于细胞输送的短,但从内分泌体中实现有效的细胞溶液释放是一个重大障碍.
- 现有的增强输送策略包括质子海绵效应,膜破坏和聚合.
研究的目的:
- 通过使用人类乳二衍生CPP (hLF-CPP) 改善mRNA输送的研究策略.
- 评估结合histidines (用于质子海绵效应),PepFect14 (PF14) 的膜活性基因和寡合化对CPP介导输送的影响.
- 确定适用于各种纳米医学平台的基于CPP的交付的总体原则.
主要方法:
- 修改了人体乳费林衍生的CPP,通过结合histidine残留物来诱导质子海绵效应.
- 引入了来自CPP的结构图案PepFect14 (PF14),已知可以破坏膜.
- 研究了寡合化对多重复的稳定性和细胞传递的影响.
- 评估修改后CPPs的细胞吸收和mRNA传递效率.
主要成果:
- 寡合化增强了多复合体的稳定性,但没有产生显著的活性.
- 添加歇斯蒂丁残留物并没有提高输送效率.
- 用类似于PF14的lysine或ornithine残留物取代 arginine对分娩没有影响.
- 通过将PF14的两性情节序列动机转移到hLF-CPP环境中,可以实现有效的mRNA传递.
- 当与转移的动机相结合时,寡合化显示出一些好处.
结论:
- 通过CPPs有效的细胞质传递ONs需要特定的结构特征,特别是膜活性基因.
- 质子海绵效应和简单的寡合化本身不足以增强CPP介导的输送.
- 从高效的CPP转移功能序列动图是一种可行的策略,可以改善不太活跃的CPP的交付.
- 结果为优化CPP,脂质纳米颗粒和其他聚合物输送系统的设计原则提供了见解.
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