美国哈佛大学Elliot L. Chaikof小组在研究中取得进展。他们研究出自组装蛋白质纳米颗粒的细胞质输送核酸和蛋白质。该项研究成果发表在2025年5月15日出版的《自然—生物技术》上。

在这里，研究组报告了用于治疗递送的弹性蛋白基纳米颗粒（ENTER）的发展，这是一种基于重组弹性蛋白样多肽（ELP）的递送系统，可在体外和体内有效地向细胞内递送生物大分子。通过迭代设计，小组开发了以阳离子内体逃逸肽（EEPs）为主题的第五代ELPs，其自组装成pH响应胶束纳米颗粒，并在内吞摄取后使货物进入细胞质。

通过对α-螺旋肽库的硅筛选，发现了一种EEP (EEP13)，其蛋白质传递效率比它们的基准肽提高了48%。与基于脂质的转染试剂相比，他们的先导ELP-EEP13在向多种细胞系和原代细胞类型递送mRNA编码、DNA编码和蛋白形式的Cre重组酶和CRISPR基因编辑器以及短干扰RNA方面表现出类似或更好的性能。在报告小鼠中，经鼻给药ELP-EEP13联合Cre蛋白实现了肺上皮细胞的高效编辑。

据介绍，生物大分子的细胞内递送受到低效率和细胞毒性的阻碍。

附：英文原文

Title: Self-assembling protein nanoparticles for cytosolic delivery of nucleic acids and proteins

Author: Eweje, Feyisayo, Ibrahim, Vanessa, Shajii, Aram, Walsh, Michelle L., Ahmad, Kiran, Alrefai, Assma, Miyasato, Dominie, Davis, Jessie R., Ham, Hyunok, Li, Kaicheng, Roehrl, Michael, Haller, Carolyn A., Liu, David R., Chen, Jiaxuan, Chaikof, Elliot L.

Issue&Volume: 2025-05-15

Abstract: Intracellular delivery of biomacromolecules is hampered by low efficiency and cytotoxicity. Here we report the development of elastin-based nanoparticles for therapeutic delivery (ENTER), a recombinant elastin-like polypeptide (ELP)-based delivery system for effective cytosolic delivery of biomacromolecules in vitro and in vivo. Through iterative design, we developed fourth-generation ELPs fused to cationic endosomal escape peptides (EEPs) that self-assemble into pH-responsive micellar nanoparticles and enable cytosolic entry of cargo following endocytic uptake. In silico screening of α-helical peptide libraries led to the discovery of an EEP (EEP13) with 48% improved protein delivery efficiency versus a benchmark peptide. Our lead ELP–EEP13 showed similar or superior performance compared to lipid-based transfection reagents in the delivery of mRNA-encoded, DNA-encoded and protein-form Cre recombinase and CRISPR gene editors as well as short interfering RNAs to multiple cell lines and primary cell types. Intranasal administration of ELP–EEP13 combined with Cre protein achieved efficient editing of lung epithelial cells in reporter mice.

DOI: 10.1038/s41587-025-02664-2

Source: https://www.nature.com/articles/s41587-025-02664-2