2. Academic Validation
  3. Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo

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

  • Nat Commun. 2021 Aug 26;12(1):5131. doi: 10.1038/s41467-021-25448-z.
Siyuan Yu  # 1,  Han Yang  # 1,  Tingdong Li  # 1,  Haifeng Pan  # 1,  Shuling Ren 1,  Guoxing Luo 1,  Jinlu Jiang 1,  Linqi Yu 1,  Binbing Chen 1,  Yali Zhang 1,  Shaojuan Wang 1,  Rui Tian 1,  Tianying Zhang 1,  Shiyin Zhang 1,  Yixin Chen 1,  Quan Yuan 2,  Shengxiang Ge 3,  Jun Zhang 1,  Ningshao Xia 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Centers of Biological Products, School of Public Health, Xiamen University, Xiamen, China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Centers of Biological Products, School of Public Health, Xiamen University, Xiamen, China. yuanquan@xmu.edu.cn.
  • 3 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Centers of Biological Products, School of Public Health, Xiamen University, Xiamen, China. sxge@xmu.edu.cn.
  • 4 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Centers of Biological Products, School of Public Health, Xiamen University, Xiamen, China. nsxia@xmu.edu.cn.
  • # Contributed equally.
PMID: 34446736 DOI: 10.1038/s41467-021-25448-z
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.

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