Penetrating peptides: Applications in drug delivery

Cell-penetrating peptides (CPPs) have gained prominence in intracellular drug delivery due to their extremely low toxicity and rapid cell internalization property. They present a powerful strategy for overcoming the plasma membrane barrier and improving the cellular uptake of multiple macromolecular drugs (siRNA, DNA, protein, and drug carriers). Nevertheless, the disadvantages of degradation by hydrolytic enzymes and lack of target selectivity have limited their applications. The development of artificial CPPs has provided an optimized sequence and spatial structure to overcome the mentioned challenges while retaining their biological activities. Owing to the diversity of CPPs, generalization of their cell-penetration mechanism is difficult. However, factors that affect CPP penetration, such as charge, pH, concentration, and temperature, are increasingly being studied. Delivery using CPPs, represented by cationic peptides, involves sequential penetration of the entire thickness of tissues to achieve cell targeting and drug release. Novel CPPs and intelligent-responsive CPP-mediated drug delivery systems have been developed simultaneously to realize the purposes of selective penetration and targeted delivery. This review highlights the application, progress, mechanism and prospect of CPPs in the process of penetrating the barrier, and discusses the most up-to-date advances of CPPs in intracellular drug delivery for targeted therapy.