Combinatorial modification of degradable polymers enables transfection of human cells comparable to adenovirus

End-modified poly(beta-amino ester)s, easy-to-synthesize degradable polymers, are able to deliver DNA to primary human cells at levels comparable to adenovirus and two orders of magnitude better than the commonly used non-viral vector, polyethylenimine. Small structural changes are found to affect multiple steps of gene delivery including the DNA binding affinity, nanoparticle size, intracellular DNA uptake, and final protein expression. In vivo, these polymer modifications enhance DNA delivery to ovarian tumors.