Abstract
A biomembrane's role is to be a barrier for interior cytosol from an exterior environment to execute the cell's normal biological functions. However, a water-soluble peptide called cell-penetrating peptide (CPP) has been known for its ability to directly penetrate through the biomembranes into cells (cytolysis) without perturbating cell viability and expected to be a promising drug delivery vector. Examples of CPP include peptides with multiple arginine units with strong cationic properties, which is the key to cytolysis. Here we show the conclusive evidence to support the mechanism of CPP’s cytolysis and way to control it. The mechanism we proposed is attributed to biomembrane’s physicochemical nature as lamellar liquid crystal (Lα). Cytolysis occurs as the temporal and local dynamic phase transitions from Lα to an undulated lamellar with pores called Mesh1. We have shown this phase transfer of Lα composed of dioleoyl-phosphatidylcholine (DOPC) with water by adding oligo-arginine (Rx) as CPP at the equilibrium. Using giant unilamellar vesicle composed of DOPC as a single cell model, we could control the level of cytolysis of CPP (FITC-R8) by changing the curvature of the membrane through osmotic pressure modulation. The cytolysis of CPP utilizes biomembrane's inherent topological and functional flexibility corresponding to the stimuli.
Highlights
A biomembrane’s role is to be a barrier for interior cytosol from an exterior environment to execute the cell’s normal biological functions
The SP value is determined by the structure of amphiphile and expressed as SP = v/(a × l) (Eq 1), where a is the cross-sectional area per molecule at the hydrophilic-hydrophobic interface, l is the length of hydrophobic parts and v is the volume of hydrophobic parts shown as Supplementary Fig. S1
In order to clarify whether cell-penetrating peptide (CPP) could make membrane curvature positive by reducing SP value, we have investigated the effect of oligo-arginine (Rx) on the phase structure of liquid crystal (LC) composed of dioleoyl-phos
Summary
A biomembrane’s role is to be a barrier for interior cytosol from an exterior environment to execute the cell’s normal biological functions. Cytolysis occurs as the temporal and local dynamic phase transitions from Lα to an undulated lamellar with pores called Mesh[1]. Lα as planar lamellar layers has zero mean curvature and slight curvature modification toward positive leads to bi-continuous cubic phase (V1) where water and lipid are independently interconnected This phase transition sometimes occurs through a meta-stable mesh phase ( Mesh1), which consists of undulated bilayers with an array of pores of catenoid structure with saddle-splay negative Gaussian curvature (Fig. S1c)[8]. Through the local pore structure of Mesh[1], a strongly cationic CPP interacting with phosphate anion can move into the interior cytosol (Fig. 1c), released into the cytosol, and the membrane returns to Lα (Fig. 1d) Because this phase change is local and temporal within the fluctuation of lipid molecules as LC, there would be no pores remaining afterward. If the wall (membrane) is resistant to changing its curvature, Mr D (the CPP) will have difficulty walking through the wall (penetrating the membrane)
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