CPP-mediated delivery into living cells has become recognized as a powerful tool for cellular trafficking and as a promising building block in drug delivery vehicles. The cellular transduction of a wide range of cargos has been accomplished by simply conjugating a cargo of interest to a CPP. However, there are still some major challenges to be overcome before CPPs can be employed for pharmaceutical use. E.g. the CPPs’ often highly positive charge can interact with blood components and enhance clearance. Moreover, they give rise to nonspecific interactions and uncontrolled uptake in non-target cells. To be able to control the activity of CPPs we have developed CPPs that can be activated by an external trigger.
In one approach we designed a UV-activatable CPP which is inactivated by means of constraining the peptide by ‘hiding’ it on the surface of a liposome and showed that this delivery system could be activated by irradiation with UV-light and be used to deliver the cytostatic agent doxorubicin into HeLa cells.¹ 
In a second method we employed non-covalent interactions to conjugate a CPP to a target protein and induce cellular uptake. We connected a CPP to one part of a hetero-dimer leucine zipper pair and showed that addition of this conjugate to a protein that was modified with a complementary leucine zipper led to uptake of this protein.² 
In a third approach we designed an activatable CPP system based on the formation of a disulfide bridge. To this purpose we have divided a CPP into two parts that by themselves do not have any cellular transduction activity. However, upon reconstitution by joining these fragments we were able to restore the CPP’s biological activity.
We believe that these methods to (in)activate CPPs can become useful tools that can be employed for controlled uptake of proteins and liposomes.