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A dual stimulus-responsive mPEG-SS-PLL15-glutaraldehydestar (mPEG-SS-PLL15-star) catiomer is developed and biologicallyevaluated. The catiomer system combines redox-sensitive removal ofan external PEG shell with acid-induced escape from the endosomalcompartment. The design rationale for PEG shell removal is to augmentintracellular uptake of mPEG-SS-PLL15-star/DNA complexesin the presence of tumor-relevant glutathione (GSH) concentration,while the acid-induced dissociation is to accelerate the release ofgenetic payload following successful internalization into targetedcells. Size alterations of complexes in the presence of 10 mM GSHsuggest stimulus-induced shedding of external PEG layers under redoxconditions that intracellularly present in the tumor microenvironment.Dynamic laser light scattering experiments under endosomal pH conditionsshow rapid destabilization of mPEG-SS-PLL15-star/DNA complexesthat is followed by facilitating efficient release of encapsulatedDNA, as demonstrated by agarose gel electrophoresis. Biological efficacyassessment using pEGFP-C1 plasmid DNA encoding green fluorescenceprotein and pGL-3 plasmid DNA encoding luciferase as reporter genesindicate comparable transfection efficiency of 293T cells of the catiomerwith a conventional polyethyleneimine (bPEI-25k)-based gene deliverysystem. These experimental results show that mPEG-SS-PLL15-star represents a promising design for future nonviral gene deliveryapplications with high DNA binding ability, low cytotoxicity, andhigh transfection efficiency. [ABSTRACT FROM AUTHOR]