In order to determine whether differences in biological activity could be explained by differences in intracellular trafficking, we deliberately permeabilized cells by a brief treatment with saponin, using conditions known to have little impact on the internal cellular architecture (22) . Saponin treatment clearly lead to a complete re-localization of FAM-labeled conjugates ( Figure 6 and data not shown) from a dotted cytoplasmic to an homogeneous nuclear distribution in keeping with a direct membrane translocation in the presence of saponin and an endocytic process in its absence. As expected from these data, splicing correction efficiency was largely increased in saponin-treated cells for all (R-X-R) 4 -PMO (Figure 7 and data not shown) thus indicating that retention within cytoplasmic vesicles remains a major road-block even for the most active of our conjugates.