Recent Progress to Explore the Mechanism of Direct Internalization of Cell-Penetrating Peptide (CPP) through BioMembrane

Abstract

A specific series of peptides, called a cell-penetrating peptide (CPP), is known to be free to directly permeate through cell membranes into the cytosol (cytolysis); hence, this CPP would be a potent carrier for a drug delivery system (DDS). Previously, we proposed the mechanism of cytolysis as a temporal and local phase transfer of membrane lipid caused by positive membrane curvature generation. Moreover, we showed how to control the CPP cytolysis based on the mechanism. Here, we introduce key factors effectively modulate the CPC cytolysis so that they could be potent tools to control cytolysis. This short communication gives overview of our progressive investigation on the CPC cytolysis mechanism which inspired us to imagine many ways to control the cytolysis either to enhance or to suppress by maneuvering membrane curvatures corresponding to the temporal phase transitions of self-assembled membrane lipids under the liquid crystal states. We have shown the usefulness of physical stimuli such as osmotic pressure or particle size and chemical stimuli with their Hoffmeister effect to the outer medium by changing the hydration level of outer layers of membrane to control the CPP cytolysis by changing membrane curvature. Taking all the revealed vital factors and their effects as a tool, we will further explore how to control CPP cytolysis for developing a DDS system combined with appropriate cargo selection to be tagged with CPPs.