Cellular uptake of arginine-rich cell-penetrating peptides and the contribution of Membrane-associated proteoglycans

Abstract

Intracellular delivery using cell-penetrating peptides (CPPs) has received considerable interest due to its ease of administration, as well as potential applicability therapeutically. Various bioactive molecules—including peptides/proteins, nucleic acids, liposomes, and nano-particles—that have been conjugated chemically to or have formed complexes with CPPs have been delivered into cells efficiently by the simple addition of these conjugates or complexes to culture media. Although various CPPs with different physicochemical properties have been reported, those rich in arginine are employed most frequently. Membrane-associated proteoglycans such as heparan sulfate proteoglycans play important roles in stimulating the cellular uptake of arginine-rich CPPs and their attached cargoes by concentrating them on cell surfaces via electrostatic interactions between the positive charge on the arginine and negative charges on the glycosaminoglycans. The interaction between arginine-rich CPPs and membrane-associate proteoglycans also induces fluid-phase endocytosis, named macropinocytosis, which facilitates the cellular uptake of arginine-rich CPPs and their cargoes.