By virtue of their RNA degrading catalytic activity, ribonucleases are potentially cytotoxic. For the application of these enzymes as therapeutics, however, they have to overcome several obstacles whose interplay is not yet fully understood. Ribonucleases with a basic pI are not only able to interact with the (negatively charged) cellular membrane but they are also distinctively selective for tumor cells. After the (endocytotic) uptake into the cell and release into the cytosol from the endosomes where they have to resist the attack by proteases, they face the cytosolic ribonuclease inhibitor. Only if they are able to evade the tight binding to the inhibitor (or if enough ribonuclease molecules enter the cell to neutralize the inhibitor protein) they are able to attack their target RNA, for which a sufficient ribonucleolytic activity is indispensable. Each of these steps can turn into an insurmountable hurdle spoiling the cytotoxic potential of these enzymes. In the present review I will summarize the status quo of the knowledge on the mechanisms and their interdependence as well as to develop strategies to overcome possible limitations.
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