英国牛津大学Katherine A. Vallis小组开发出一种三环细胞穿透肽，可将与其连接的功能性抗体高效递送至癌细胞。相关论文于2022年2月10日发表于国际顶尖学术期刊《自然-化学》杂志上。

在该研究中，团队利用一种三聚体细胞穿透肽（CPP），将抗体和抗体片段递送到细胞质和核中。研究人员发现，基于经典穿膜肽Tat的线性和环状序列的四种三聚体明显比对应的单体更有效，而且还可以通过直接与质膜相互作用或从囊泡样体逃逸来调节其功能。该研究发现了一个三环Tat结构，能够向细胞内递送功能性免疫球蛋白G抗体和Fab片段，这些载荷可以在有效浓度低至1μM时结合活细胞细胞质和细胞核内的靶标。

据了解，细胞内环境承载着大量的癌症和其他疾病相关的人类蛋白质。用可内吞的抗体来靶向这些蛋白质可以对迄今为止无药可用的通路（如蛋白质-蛋白质相互作用介导的通路）进行治疗性调节。然而，细胞内靶向的主要障碍之一是生物大分子会在内吞体中被捕获。

附：英文原文

Title: Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells

Author: Tietz, Ole, Cortezon-Tamarit, Fernando, Chalk, Rod, Able, Sarah, Vallis, Katherine A.

Issue&Volume: 2022-02-10

Abstract: The intracellular environment hosts a large number of cancer- and other disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein–protein interactions. However, one of the major obstacles in intracellular targeting is the entrapment of biomacromolecules in the endosome. Here we report an approach to delivering antibodies and antibody fragments into the cytosol and nucleus of cells using trimeric cell-penetrating peptides (CPPs). Four trimers, based on linear and cyclic sequences of the archetypal CPP Tat, are significantly more potent than monomers and can be tuned to function by direct interaction with the plasma membrane or escape from vesicle-like bodies. These studies identify a tricyclic Tat construct that enables intracellular delivery of functional immunoglobulin-G antibodies and Fab fragments that bind intracellular targets in the cytosol and nuclei of live cells at effective concentrations as low as 1μM.

DOI: 10.1038/s41557-021-00866-0

Source: https://www.nature.com/articles/s41557-021-00866-0