Cell-Penetrating Peptides: Features, Mechanisms, Applications

Cell-penetrating peptides (CPPs) refer to water-soluble, partly hydrophobic, and/or polybasic short peptides that are fewer than 30 amino acids in size. Different types of CPPs like chimeric peptides and hydrophobic peptides have different lengths, charges, solubility, and hydrophobicity. At current, cell-penetrating peptides are often classified in line with their characteristics, including origin, conformation, and chemical properties. Although CPPs are highly diverse in physicochemical and biological properties, they have some properties in common. For example, they are positively charged because of their high content of basic amino acids. Other CPPs present additional advantages such as tumor-homing, penetration through the blood-brain barrier, and antimicrobial activity.


  • Features

The most remarkable feature of cell-penetrating peptides is that it’s able to penetrate the cell membrane at low micromolar concentrations in vivo and in vitro, without using any chiral receptors and without causing significant membrane damage. They can promote cellular intake and uptake of molecules ranging from small chemical compounds to large fragments of DNA. However, there is still considerable debate about the mechanism of cellular uptake, which is mainly related to the nature of CPPs or transported cargoes, experimental conditions such as pH and temperature, cell types, etc. It seems to be the consensus for various CPPs or CPP/cargoes internalization mechanisms that cellular uptake of CPPs or CPP/cargoes is generally divided into direct translocation and endocytosis, depending on whether energy is required or not in the process of internalization. 


  • Mechanisms

Direct translocation occurs initially through electrostatic interaction or hydrogen bonding between phospholipid bilayer and CPPs or CPP/cargoes. The interaction is followed by CPPs or CPP/cargoes entrance via pore formation or membrane destabilization. Direct translocation is most suitable for CPPs or CPPs associated with small cargo entering the cell, while large molecules weight CPPs or CPP/cargoes mainly depend on endocytosis. So far, endocytosis is described in four different pathways encompassing caveolin-mediated endocytosis, micropinocytosis, clathrin-mediated endocytosis, and clathrin- and caveolin-independent endocytosis. It has been demonstrated that energy-dependence endocytosis is the prevailing cellular uptake mechanism for large molecules weight CPPs or CPP/cargoes.


  • Applications

In general, CPPs are often passive and nonselective. As a result, they must be functionalized or chemically modified to create effective delivery vectors that succeed in targeting specific cells or tissues. Excitingly, these versatile peptides are simple to synthesize, functionalize, and characterize yet can deliver covalently or noncovalently conjugated bioactive cargos inside cells, primarily via endocytosis, to obtain high levels of gene expression, gene silencing, or tumor targeting. There are several ways to improve the pharmacological properties of known CPPs. Chemical modifications or the redesigning of CPPs are the most common approaches used to enhance cellular uptake and selectivity, as well as stability, for a longer half-life in circulation. The most frequently applied alterations concerning CPPs encompass PEGylation, cyclization, N-terminal stearylation, etc.


CPPs have proven to be powerful transport vectors for intracellular delivery of a wide variety of cargoes across cell membranes. They not only transfer themselves into cells but also deliver protein, siRNA, antisense oligonucleotide, nanoparticles, PNA, liposomes, and nucleic acids. In addition, CPPs also play a significantly important role in the delivery of imaging agents, due to their excellent permeability, high affinity, and high stability, with potential applications in the diagnosis and therapy of diseases such as cancer, inflammation, diabetes, central nervous system diseases, and otologic and ocular disorders. Therefore, the number of CPPs under clinic evaluation is expected to grow. 


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