New Sequence-Defined Polyaminoamides with Tailored Endosomolytic Properties for Plasmid DNA Delivery

Heterogeneity of polymeric carriers is one of the most elusive obstacles in the development of nonviral gene delivery systems, concealing interaction mechanisms and limiting the use of structure–activity relationship studies. In this report, novel sequence-defined polyaminoamides, prepared by solid-phase assisted synthesis, were used to establish first structure–activity relationships for polymer-based plasmid DNA delivery. By combining a cationic building block with hydrophobic modifications and bioreversible disulfide cross-linking sites, transfection polymers with tailored lytic and DNA binding properties were designed. These polymers demonstrated clear correlation between structure and performance in lysis and DNA binding assays. In vitro studies showed negligible toxicity and highly efficient gene transfer, demonstrating the potential of this platform in the fast, combinatorial development of new transfection polymers.