As one of the toughest tasks in the course of intracellular therapeutics delivery, endosomal escape must be effectively achieved, particularly for intracellular gene transport. In this report, novel endosomal-escape polymers were designed and synthesized from monomers by integrating alkyl and imidazolyl via Passerini reaction and reversible addition–fragmentation chain transfer polymerization (RAFT). After introducing the endosomal-escape polymers with proper degrees of polymerization (DPs) into poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) as the gene delivery vectors, the block copolymers exhibited significantly enhanced hemolytic activity at endosomal pH, and the plasmid DNA (pDNA)-loaded polyplexes showed efficient endosomal escape compared with PDMAEMA, ultimately achieving dramatically increased gene transfection efficacy. These results suggest that the polymers that integrate alkyl and imidazolyl moieties for efficient endosomal escape have wide potential applications for intracellular gene delivery.