2. Academic Validation
  3. Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay

Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay

  • Nat Commun. 2021 Jun 17;12(1):3721. doi: 10.1038/s41467-021-23997-x.
Serena L Y Teo # 1 2,  Joshua J Rennick # 1 2,  Daniel Yuen 1 2,  Hareth Al-Wassiti 1,  Angus P R Johnston 3 4,  Colin W Pouton 5
Affiliations

Affiliations

  • 1 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • 2 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, VIC, Australia.
  • 3 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. angus.johnston@monash.edu.
  • 4 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, VIC, Australia. angus.johnston@monash.edu.
  • 5 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. colin.pouton@monash.edu.
  • # Contributed equally.
PMID: 34140497 DOI: 10.1038/s41467-021-23997-x
Abstract

Cytosolic transport is an essential requirement but a major obstacle to efficient delivery of Therapeutic Peptides, proteins and nucleic acids. Current understanding of cytosolic delivery mechanisms remains limited due to a significant number of conflicting reports, which are compounded by low sensitivity and indirect assays. To resolve this, we develop a highly sensitive Split Luciferase Endosomal Escape Quantification (SLEEQ) assay to probe mechanisms of cytosolic delivery. We apply SLEEQ to evaluate the cytosolic delivery of a range of widely studied Cell-penetrating Peptides (CPPs) fused to a model protein. We demonstrate that positively charged CPPs enhance cytosolic delivery as a result of increased non-specific cell membrane association, rather than increased endosomal escape efficiency. These findings transform our current understanding of how CPPs increase cytosolic delivery. SLEEQ is a powerful tool that addresses fundamental questions in intracellular Drug Delivery and will significantly improve the way Materials are engineered to increase therapeutic delivery to the cytosol.

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