Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

Cell-penetrating peptides (CPPs) have been discovered to deliver chemical drugs, nucleic acids, and macromolecules to permeate cell membranes, creating a novel route for exogenous substances to enter cells. Up until now, various sequence structures and fundamental action mechanisms of CPPs have been established. Among them, arginine-rich peptides with unique cell penetration properties have attracted substantial scientific attention. Due to the positively charged essential amino acids of the arginine-rich peptides, they can interact with negatively charged drug molecules and cell membranes through non-covalent interaction, including electrostatic interactions. Significantly, the sequence design and the penetrating mechanisms are critical. In this brief synopsis, we summarize the transmembrane processes and mechanisms of arginine-rich peptides; and outline the relationship between the function of arginine-rich peptides and the number of arginine residues, arginine optical isomers, primary sequence, secondary and ternary structures, etc. Taking advantage of the penetration ability, biomedical applications of arginine-rich peptides have been refreshed, including drug/RNA delivery systems, biosensors, and blood-brain barrier (BBB) penetration. Understanding the membrane internalization mechanisms and design strategies of CPPs will expand their potential applications in clinical trials.