4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25448-z

Keywords

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Funding

  1. Ministry of Science and Technology of China [2020YFC1316800]
  2. National Natural Science Foundation of China [31971369]
  3. National Key Programme for Infectious Disease of China [2018ZX10732401-003-008]
  4. Natural Science Foundation of Fujian Province of China [2019J02004]

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The authors present an intracellular protein delivery system that overcomes the limitations of ineffective endosomal escape and low serum tolerance associated with cell-penetrating peptide-mediated protein delivery. This system shows efficient delivery and therapeutic efficacy in a liver failure model, highlighting the potential of using multifunctional chimaeric peptides for developing cell-penetrating peptide-based protein delivery systems.
Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo. 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-alpha-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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