Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA). Many issues should be addressed before translating CPPs into clinics. In this review, we summarize recent developments and innovations in preclinical studies and clinical trials based on using CPP for improved delivery, which have revealed that CPPs or CPP-based delivery systems present outstanding diagnostic therapeutic delivery potential.

Based on their origins, CPPs can be divided into protein-derived CPPs, synthetic CPPs, and chimeric CPPs. (1). Protein-derived CPPs, including the TAT protein (Vives et al., 1997) and penetratin (Derossi et al., 1994), can enter the cell because they have a specific motifs or helical structures (Traub, 2009). (2). Synthetic CPPs. In this group, polyarginine 8-10-mers are most widely studied because of their high efficiency in cellular uptake (Mitchell et al., 2000). (3). Chimeric CPPs. This group of CPPs is generally recognized as a transition from natural to synthetic CPPs since they contain sequences from two or more different naturally occurring proteins. Examples include amphipathic peptide (CADY) (20 amino acids) which combines aromatic residue (Tryptophan, W) and cationic residue (Arginine, R) (Crombez et al., 2009). (Front Pharmacol. 2020; 11: 697.)