Mechanisms of Cellular Uptake of Cell-Penetrating Peptides

TLDR

Cell‑penetrating peptides (CPPs), rich in basic residues, have emerged as promising agents for delivering large cargoes across cell membranes, yet the precise molecular uptake mechanisms, toxicity, and delivery efficiency remain debated. This review aims to examine the uptake mechanisms employed by CPPs for membrane translocation and to evaluate experimental factors that influence these processes. The authors synthesize evidence on endocytosis and direct penetration pathways, discussing how experimental variables modulate CPP uptake efficiency.

Abstract

Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s).