Non-viral vectors for in vivo delivery of plasmid DNA rely on optimized formulations to achieve robust transgene expression. Several cationic lipids have been developed to deliver nucleic acids, but most recent literature has focused on mRNA due to its increased expression profile and excluded plasmid DNA, which may have the advantage of being less immunogenic. In this study, we describe the in vivo evaluation of cationic triazine based lipids, previously prepared by our group. We identify one lipid with limited in vivo toxicity for studies to optimize the lipid formulations, which include an evaluation of the influence of PEG and helper lipids on transgene expression. We then demonstrate that lipoplexes, but not lipid nanoparticles, formed from triazine lipids achieve similar transgene expression levels as AAV vectors and offer enhanced expression as compared to a commercially available cationic lipid, DOTAP. Importantly, the lipid nanoparticles and lipoplexes induce minimal antibody profiles toward the expressed protein, while serving as a platform to induce robust antibody responses when directly delivering the protein. Collectively, these data demonstrate the potential for triazine based lipids as non-viral vectors for gene delivery, and highlights the need to optimize each formulation based on the exact contents to achieve enhanced transgene expression with plasmid DNA constructs.