A primary challenge in the development of RNAi therapeutics is delivering the RNAi trigger molecules into the cytoplasm of the cell where RNAi activity occurs. Dynamic PolyConjugates (DPC’s) are Arrowhead’s innovative delivery system engineered specifically to induce efficient endosomal escape. The endosomal release is facilitated by a peptide that is reversibly-masked for reduced non-specific interactions during in vivo circulation, and is actively targeted to the desired cell type through efficient receptor binding. Here we present an example of the DPC platform composed of a hepatocyte-targeted endosome-releasing agent and a cholesterol-conjugated siRNA. This delivery platform forms the basis of ARC-520, an siRNA-based therapeutic for the treatment of chronic hepatitis B virus (HBV) infection. DPC’s have demonstrated rapid, deep and durable knockdown of target genes expressed in the liver and has been well tolerated in clinical trials.