Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide

Misao Akishiba, Toshihide Takeuchi, Yoshimasa Kawaguchi, Kentarou Sakamoto, Hao Hsin Yu, Ikuhiko Nakase, Tomoka Takatani-Nakase, Fatemeh Madani, Astrid Gräslund, Shiroh Futaki

Research output: Contribution to journalArticlepeer-review

172 Citations (Scopus)

Abstract

One of the major obstacles in intracellular targeting using antibodies is their limited release from endosomes into the cytosol. Here we report an approach to deliver proteins, which include antibodies, into cells by using endosomolytic peptides derived from the cationic and membrane-lytic spider venom peptide M-lycotoxin. The delivery peptides were developed by introducing one or two glutamic acid residues into the hydrophobic face. One peptide with the substitution of leucine by glutamic acid (L17E) was shown to enable a marked cytosolic liberation of antibodies (immunoglobulins G (IgGs)) from endosomes. The predominant membrane-perturbation mechanism of this peptide is the preferential disruption of negatively charged membranes (endosomal membranes) over neutral membranes (plasma membranes), and the endosomolytic peptide promotes the uptake by inducing macropinocytosis. The fidelity of this approach was confirmed through the intracellular delivery of a ribosome-inactivation protein (saporin), Cre recombinase and IgG delivery, which resulted in a specific labelling of the cytosolic proteins and subsequent suppression of the glucocorticoid receptor-mediated transcription. We also demonstrate the L17E-mediated cytosolic delivery of exosome-encapsulated proteins.

Original languageEnglish
Pages (from-to)751-761
Number of pages11
JournalNature Chemistry
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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