Overcoming Cellular Barriers with Cell-Penetrating Peptides: Functional Roles of Individual Amino Acids

The delivery efficiency of cell-penetrating peptides (CPPs) is much lower than that of other non-viral delivery systems, mainly because of cellular barriers such as the plasma membrane, endosomal acidification, cytosolic degradation, and nuclear entry. The plasma membrane is a significant extracellular barrier that regulates the entry of biomolecules into cells. This challenge can be addressed by using peptides containing functional groups, such as basic amino acids. After internalization, CPPs must cross intercellular barriers, and their ability to do so mainly depends on the specific amino acids making up the peptide. For instance, histidine helps with endosomal escape. Conversely, the presence of a nuclear localization signal increases the likelihood of CPPs entering the nucleus. Overcoming these barriers depends on the presence and position of specific amino acid residues within a CPP. We focus on how the functional properties of these amino acids facilitate the overcoming of cellular barriers, thereby improving biomolecular delivery. We also discuss some CPPs that have advanced to clinical trials and highlight their strengths.