siRNA has been used to silence many genes in a variety of cell types with high specificity and is of great interest as a cancer therapeutic. siRNA, similar to other macromolecular drugs, once endocytosed, is predominantly trafficked to the lysosome and degraded enzymatically. In addition, serum proteases are capable of rapid siRNA degradation. Therefore, an optimal therapeutic siRNA delivery approach would combine serum-stability, long circulation times, and tissue-specific targeting, with efficient endosomal uptake and escape prior to lysosomal trafficking. Previously, we developed a carrier that addressed serum-stability and endosomal uptake and escape. This carrier, polymerized via reversible addition fragmentation chain transfer polymerization, combines positively-charged dimethylaminoethyl methacrylate (DMAEMA) as a siRNA-condensing block with a pH-responsive block to enable endosomal escape. To further develop our therapeutic approach, we have utilized a novel chain-extension polymerization technique to include either folate or lactose targeting moieties to (1) increase in vitro uptake by target cells and subsequent knockdown efficiency and (2) reduce in vivo dosing. Therefore, by introducing specific targeting moieties enabling receptor-mediated versus non-specific endocytosis, siRNA effects can be augmented.