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A novel class of cationic hyperbranched polymers, containing branched oligoethylenimine (OEI 800 Da) as core, diacrylate esters as linkers and oligoamines as surface modification, was synthesized and evaluated regarding their structure–activity relationship as gene carriers. We show that pseudodendritic core characteristics as well as different surface modifications on the core influence DNA-binding ability, cytotoxicity and transfection efficiency. As most promising gene carrier, the pseudodendrimer HD O, that is, the OEI 800 Da core modified with hexane-1,6-diol diacrylate and surface-modified with OEI 800 Da, was identified. HD O exhibits efficient DNA-condensing ability to nanosized polyplexes (100–200 nm), low cytotoxicity, a degradation half-life of 3 days at 37 °C at physiological pH and in vitro reporter gene-expression levels similar to high molecular weight linear and branched polyethylenimines (PEIs) (LPEI and BPEI). In vivo studies in mice reveal that HD O/DNA polyplexes upon i.v. tail-vein injection have the potential for transfection of tumor tissue at levels comparable to that obtained with LPEI. Importantly, HD O was better tolerated than LPEI, while transgene expression was more tumor-specific and much lower in all other investigated organs, especially in the lung (15 000-fold lower compared with LPEI).Gene Therapy (2008) 15, 18–29; doi:10.1038/sj.gt.3303046; published online 25 October 2007 [ABSTRACT FROM AUTHOR]