Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), are short sequences of amino acids that are able to penetrate cell membranes and facilitate the intracellular delivery of various cargos such as peptides, proteins, nucleic acids and nanoparticles. Some of the first CPPs identified include the HIV-1 Tat protein transduction domain and penetratin which is derived from the homeodomain of the Drosophila antennapedia transcription factor.

Mechanisms of Cell Entry

There are two major proposed mechanisms for the cell membrane permeability of CPPs - endocytosis and direct translocation. For endocytosis, it is thought that the CPP interacts electrostatically with proteoglycans on the cell surface which triggers invagination and formation of endosomes containing the internalized Cell Penetrating Peptides. The endosome must then fuse with endolysosomes to enable cargo escape into the cytosol for functional delivery. Direct translocation involves the formation of transient membrane pores by the CPP that allow direct passage across the lipid bilayer and into the cytosol. The exact mechanism depends on factors like CPP and cargo properties as well as cell type.

Therapeutic Applications of CPPs

One of the most promising applications of CPPs is for intracellular drug delivery to overcome issues like poor cellular uptake and endosomal entrapment that hamper conventional drug therapies. For instance, CPPs can deliver protein drugs, oligonucleotides and siRNAs that are otherwise difficult to introduce into living cells. Some examples of cell penetrating peptides used for therapeutic delivery include:

- Tat peptide - Used to deliver cytotoxic drugs, protein biologics and nanoparticles for cancer therapy. Clinical trials show efficacy for retinal disease treatment.

- Penetratin - Enhances cellular delivery of antibodies, enzymes and DNA/RNA for therapeutic gene editing and vaccination applications.

- Transportan - Emerging applications include delivery of nucleic acids, adjuvants and nanoparticles for immunotherapy and vaccine development.

- PepFect14 - Enables delivery of CRISPR-Cas9 genome editing machinery into difficult-to-transfect cells for investigational therapies.

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