“Trojan Horse” Peptides: Delivery Systems With Diverse Applications

The Cell Penetrating Peptide TAT from HIV 1, and others, can be used to facilitate the delivery of molecules into cells.

The Cell Penetrating Peptide TAT from HIV 1, and others, can be used to facilitate the delivery of molecules into cells.

Everyone wants to get things into cells. Biomedical researchers, clinicians and even insect biologists.

Consequently there is a large research community – primarily in the realm of biomedicine – that is actively exploring “delivery systems”.

Cell Penetrating Peptides (CPPs), sometimes referred to as “Trojan Horse” peptides, were discovered in 1989 with the characterization of the cell penetrating properties of the transactivating protein (TAT) of HIV-1. Since then many proteins with cell penetrating properties have been discovered or created, most between 5 and 30 amino acids in length, all capable of traversing plasma membranes of cells. Penetratin is a cell penetrating peptide, as well known as HIV TAT, 16-amino acids in length and part of the homeodomain protein encoded by Antennapedia from Drosophila melanogaster.

Penetratin Transport System. Image credit: Cyclacel Limited

Penetratin Transport System.
Image credit: Cyclacel Limited

Shi et al (2014) have published a fairly comprehensive review of CPPs in the Journal of Controlled Release, describing the many ways CPPs can be used as ‘delivery mediators’, reviewing in detail myriad issues associated with these proteins, including toxicity, biodistribution and translocation efficiency.  The published literature on CPPs is deep and in 2014 alone there were at least 9 review-like publications on the subjects (see below).

The reasons why CPPs should be of interest to insect biologists looking for ways to exploit currently available genetic technologies are pretty clear. The most immediate problem insects biologist face when trying to manipulate insect genotypes and phenotypes, like biomedical clinicians wishing to apply genetic or pharmaceutical solutions to their cases, is how to deliver the protein, DNA or RNA to the cells of interest.

CPPs can be covalently or non-covalently attached to 'cargo'

CPPs can be covalently or non-covalently attached to ‘cargo’

Examples of covalent linkages of CPPs to nucleic acids

Examples of covalent linkages of CPPs to nucleic acids


Lepidoptera larvae have shown variable and species-dependent responses to dsRNA injected into the hemocoel. Aphids and other Heteroptera, I am told, are similarly difficult. There are many examples like this in insect biology and consequently CPPs probably deserve more attention from insect biologists. Interestingly CPPs can be used to deliver nucleic acids using a variety of strategies.

Fruitful interactions await insect biologists and those doing research and development of CPPs for clinical use.


Shi N-Q, Qi X-R, Xiang B, Zhang Y (2014) A survey on “Trojan Horse” peptides: Opportunities, issues and controlled entry to “Troy”. J Control Release 194: 53-70   doi.org/10.1016/j.jconrel.2014.08.014


Review-like publications on Cell Penetrating Peptides in 2014:

Brock R (2014) The Uptake of Arginine-Rich Cell-Penetrating Peptides: Putting the Puzzle Together. Bioconjug Chem 25: 863-868 10.1021/bc500017t

Copolovici DM, Langel K, Eriste E, Langel U (2014) Cell-Penetrating Peptides: Design, Synthesis, and Applications. ACS Nano 8: 1972-1994 10.1021/nn4057269

de Figueiredo IR, Freire JM, Flores L, Veiga AS, Castanho M (2014) Cell-penetrating peptides: A tool for effective delivery in gene-targeted therapies. IUBMB Life 66: 182-194 10.1002/iub.1257

Farkhani SM, Valizadeh A, Karami H, Mohammadi S, Sohrabi N, Badrzadeh F (2014) Cell penetrating peptides: Efficient vectors for delivery of nanoparticles, nanocarriers, therapeutic and diagnostic molecules. Peptides 57: 78-94 10.1016/j.peptides.2014.04.015

He HN, Ye JX, Wang YS, Liu Q, Chung HS, Kwon YM, Shin MC, Lee K, Yang VC (2014) Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application. J Control Release 176: 123-132 10.1016/j.jconrel.2013.12.019

Liu Y, Li JM, Tan T, Jiang Y (2014) Progress of Cell Penetrating Peptides Application as Delivery Agent. Progress in Biochemistry and Biophysics 41: 731-738 10.3724/sp.j.1206.2013.00336

Shin MC, Zhang J, Min KA, Lee K, Byun Y, David AE, He HN, Yang VC (2014) Cell-penetrating peptides: Achievements and challenges in application for cancer treatment. J Biomed Mater Res Part A 102: 575-587 10.1002/jbm.a.34859

Wang FH, Wang Y, Zhang X, Zhang WJ, Guo SR, Jin F (2014) Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery. J Control Release 174: 126-136 10.1016/j.jconrel.2013.11.020


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