Lipid modification has been widely applied to improve the gene delivery efficacy of cationic polymers. However, this strategy is often associated with relatively low efficacy and high toxicity due to the inherent features of lipids. Here, we describe a novel and facile strategy to develop polymeric gene vectors via cyclododecylation of cationic dendrimers. The synthesized cyclododecylated dendrimer is much more efficient and biocompatible than the dodecylated analogues.