Strategies to improve intracellular delivery of arginine-rich cell-penetrating peptides

Abstract

Cell-penetrating peptides (CPPs) have been shown to transport diverse cargo molecules across the cell membrane, providing a novel route for cellular uptake. Among the various CPP sequences developed to date, arginine (Arg)-rich CPPs have gained substantial attention from the scientific community. This is primarily due to their unique interactions with negatively charged cell membranes and drug molecules through non-covalent forces, such as electrostatic interactions. For such unique properties of Arg-rich CPPs, researchers have developed numerous strategies that showed possible improvement in cellular uptake for a range of cargo molecules utilizing Arg-rich CPP platforms. In this review, we highlighted the potential strategies to improve the plasma membrane-crossing competence of Arg-rich CPPs. We outline the relationship between the cellular uptake or cytosolic delivery of cargo molecules and the structural properties of Arg-rich CPPs, considering all known strategies, including covalent attachment of small-molecule scaffolds, CPP additives, etc. Taking advantage of their penetration ability, biomedical applications of Arg-rich peptides have been revitalised. This summary provides a comprehensive overview of the current state of Arg-rich CPP research. The discussion highlights existing limitations that may hinder progress and outlines potential future directions and possibilities.