Cationic polymer charge and polymer degradability each play a crucial role for packaging and delivering plasmid DNA. High density cationic charge has been shown to enhance transfection efficiency but may give rise to undesirable toxicity. Polyvinylamine (PVAm) nanogels bearing discrete amounts of surface charge were used to systematically examine the balance between transfection efficiency and cytotoxicity. Poly(N-vinylformamide) (PNVF) nanogels were prepared via an inverse emulsion polymerization reaction and crosslinked with a nondegradable or acid-labile crosslinker. The nanogels were then hydrolyzed to yield varying degrees of primary amines. The degree of conversion from PNVF to PVAm was controlled using different concentrations of NaOH and hydrolysis times. PVAm nanogel size and charge ranged from 150 to 310 rim, and +3.5 to +18 mV, respectively. These cationic particles were then complexed with pDNA encoding for luciferase. The cytotoxicity of PVAm nanogels and the transfection efficiency of PVAm/DNA complexes were evaluated in carcinomic human alveolar basal epithelial cells (A549). The cytotoxicity of PVAm nanogels increased with increasing accessible charge as expected. Transfection efficiency increased with increasing amounts of amine groups for nondegradable nanogels. Interestingly, acid-labile nanogels bearing low charge demonstrated more sustained gene transfection when compared with the more highly charged nanogels. These observations suggested that the use of degradable particles with less charge may reduce cytotoxicity without compromising overall transfection efficiency. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 118: 1921-1932, 2010