Of possible relevance, (R-Ahx-R) 4 -PMO conjugates bind less strongly to heparin (taken as a model heparan sulfate) than Tat-or (Arg) n -PMO conjugates (3) . This could provide an explanation if one assumes that heparan sulfate-bound material has to be released during endocytosis in order to escape to the cell cytoplasm. While sufficient affinity is essential for cell binding and cellular uptake, a too high affinity could become detrimental at later steps, a hypothesis which we aim to investigate here.