Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo

Siyuan Yu, Han Yang, Tingdong Li, Haifeng Pan, Shuling Ren, Guoxing Luo, Jinlu Jiang, Linqi Yu, Binbing Chen, Yali Zhang, Shaojuan Wang, Rui Tian, Tianying Zhang, Shiyin Zhang, Yixin Chen, Quan Yuan (), Shengxiang Ge (), Jun Zhang and Ningshao Xia ()
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Siyuan Yu: Xiamen University
Han Yang: Xiamen University
Tingdong Li: Xiamen University
Haifeng Pan: Xiamen University
Shuling Ren: Xiamen University
Guoxing Luo: Xiamen University
Jinlu Jiang: Xiamen University
Linqi Yu: Xiamen University
Binbing Chen: Xiamen University
Yali Zhang: Xiamen University
Shaojuan Wang: Xiamen University
Rui Tian: Xiamen University
Tianying Zhang: Xiamen University
Shiyin Zhang: Xiamen University
Yixin Chen: Xiamen University
Quan Yuan: Xiamen University
Shengxiang Ge: Xiamen University
Jun Zhang: Xiamen University
Ningshao Xia: Xiamen University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Protein delivery with cell-penetrating peptide is opening up the possibility of using targets inside cells for therapeutic or biological applications; however, cell-penetrating peptide-mediated protein delivery commonly suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting in vivo efficacy. Here, we present an intracellular protein delivery system consisting of four modules in series: cell-penetrating peptide, pH-dependent membrane active peptide, endosome-specific protease sites and a leucine zipper. This system exhibits enhanced delivery efficiency and serum tolerance, depending on proteolytic cleavage-facilitated endosomal escape and leucine zipper-based dimerisation. Intravenous injection of protein phosphatase 1B fused with this system successfully suppresses the tumour necrosis factor-α-induced systemic inflammatory response and acetaminophen-induced acute liver failure in a mouse model. We believe that the strategy of using multifunctional chimaeric peptides is valuable for the development of cell-penetrating peptide-based protein delivery systems, and facilitate the development of biological macromolecular drugs for use against intracellular targets.

Date: 2021
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DOI: 10.1038/s41467-021-25448-z

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