The rational design of cell-penetrating peptides for application in delivery systems.

Cell penetrating peptides (CPPs) play a crucial role in the transportation of bioactive molecules. Although CPPs have been used widely in various delivery systems, further applications of CPPs are hampered by several drawbacks, such as high toxicity, low delivery efficiency, proteolytic instability and poor specificity. To design CPPs with great cell-penetrating ability, physicochemical properties and safety, researchers have tried to develop new methods to overcome the defects of CPPs. Briefly, (1) the side chain of arginine containing the guanidinium group is essential for the facilitation of cellular uptake; (2) the hydrophobic counterion complex around the guanidinium-rich backbone can "coat" the highly cationic structure with lipophilic moieties and act as an activator; (3) the conformation-constrained strategy was pursued to shield the peptide, thereby impeding access of the proteolytic enzyme; (4) targeting strategies can increase cell-type specificity of CPPs. In this review, the above four aspects were discussed in detail.