In this paper, we continue our exploration of the molecular mechanisms by which PS ASOs enter and distribute within cells such that they can be pharmacologically active. We show that M6PR plays a critical role in releasing PS ASOs from late endosomes. We now believe that we have identified most of the endosomal means of productive uptake and intracellular distribution of PS ASOs. We are assessing the relative contributions of each pathway we have identified. In future papers, we hope to quantitate release kinetics from late endosomes.