Oligomeric sulfonamides (OSAs) are explored as a tool for the effective endosomal release of polyplexes or delivery of nucleic acid. The OSAs tested in this study show varying proton-buffering regions and pH-dependent solubility transitions within the endosomal pH range, and are influenced by the pK(a) value and hydrophobicity of a given sulfonamide group. In addition, OSA presents negligible toxicity. The oligomers are added to the nucleic acid solution for polyplex formation with positively charged polymeric nucleic acid carriers. ne resulting nanoscale, positively charged, and OSA-incorporated poly(L-lysine) (PLL)/DNA complexes (OSA-polyplexes) show a 4-55-fold increase in in vitro gene expression compared to PLL/DNA (control), depending upon the cell line and the nature of the used OSA. In cellular uptake and intracellular trafficking studies using pH-sensitive or pH-insensitive dye-labeled DNAs, there is no significant difference in the amount of DNA uptake using OSA polyplexes and PLL/DNA. However, OSA-polyplexes induce a broader intracellular distribution of the DNA than PLL/DNA complexes do. These results, coupled with the enhanced DNA transfection using OSA-polyplexes, indicate a mechanism by which OSA induces endosomal release of polyplexes and/or nucleic acids. The findings suggest that OSA could enhance polymer-based nucleic acid delivery. Furthermore, such materials offer significant potential for effective cytosolic delivery of chemical, biological, and diagnostic therapeutics.