Quo vadis polyplex?

Polymeric siRNA delivery has been an important field for the Journal of Controlled Release since the early 2000s. With currently about 1600 publications on this topic that can be found in Scopus, we have to ask ourselves why the clinical translation has been so slow. In this review we address the importance of in vivo studies, the problem of biocompatibility of the carrier systems, intracellular entrapment and endosomal release, as well as stability issues in the presence of serum. Most of all, we ask the question: Quo vadis? Where do polymeric carriers go inside the cell and inside the body and how does this affect repeated administration? We show that the gap of knowledge on polymer biodistribution and excretion has not been closed yet and needs to be addressed to develop safe RNAi therapeutics.