Happy birthday cell penetrating peptides: already 20 years

The recent discovery of new potent therapeutic molecules that do not reach the clinic due to poor delivery and low bioavailability has made of delivery a keystone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs). CPPs were discovered 20 years ago based on the potency of several proteins to enter cells. So far numerous CPPs have been described which can be grouped into two major classes, the first requiring chemical linkage with the drug for cellular internalization, the second involving formation of stable, non-covalent complexes with cargos. Nowadays, CPPs constitute as a very promising tool for non-invasive cellular import of cargos and have been successfully applied for ex vivo and in vivo delivery of therapeutic molecules varying from small chemical molecules, nucleic acids, proteins, peptides, liposomes to particles. This short introduction will highlight the major breakthroughs in the CPP history, which have driven these delivery agents to the clinic.