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Cationic dendrimers and polyethyleneimine (PEI) have been widely investigated both in vitro and in vivo.Generally, high generation dendrimer and high molecular weight PEI possess relatively high transfection efficacy, but they are associated with serious cytotoxicity during gene transfection.In comparison, low generation dendrimer and low molecular weight PEI has good biocompatibility but poor transfection efficacy.To break up the correlation between transfection efficacy and cytotoxicity for these cationic polymers, we design a core-shell nanostructure in which the complex of high generation (generation 8, G8) polyamidoamine dendrimer and plasmid DNA acts as a negatively charged core and low molecular weight polymer such as 1.8kD LPEI, 2.5 kD bPEI or G2 dendrimer as the shell.The core-shell nanostructure with a 1.8kD LPEI or 2.5 kD bPEI shell has a small size below 200 nm which is suitable for gene transfection Attachment of cationic shell on the G8/DNA core turns the complex charge from negative to positive.The core-shell nanostructure with 1.8kD LPEI shell shows the highest transfection efficacy compared with nanostructures with 2.5 kD bPEI and G2 dendrimer shells.Such a core-shell nanostructure fulfills the two main requirements-high transfection efficacy and low cytotoxicity in gene delivery.