It is now well admitted that basic CPPs interact with heparan sulfate-rich cell surface glycosaminoglycans before being internalized by endocytosis (19) . A sufficient affinity for these negatively charged proteoglycans is required for cell binding and for subsequent cellular uptake. On the other hand, too much affinity for heparan sulfate might be detrimental for the release of CPP-ON conjugates from endocytic vesicles as hypothesized in our previous publications (3, 10) .