Unfortunately, there is not a clear understanding of the effects the various moieties play on the myriad of polymer chemistries currently being pursued for siRNA delivery. In order to better characterize the binding step of polymer/siRNA (nanoparticle; NP) complex formation, we are using a novel polymeric system that allows addition of virtually any moiety. Through our systematic studies, we will show that binding of siRNA by the NP is strongly dependent on the cationic charge density along the backbone and that incorporation of specific functionalities can influence that binding through physical and structural changes. The observed trends also appear to be important for biocompatibility (i.e., toxicity). Together, our results can be used to identify new polymers that are designed to meet the complex requirements for siRNA delivery.