**7. Toxicity of PEI-based non-viral vector systems**

Synthetic polymers and nanomaterials display selective phenotypic effects in cells and in the body that affect signal transduction mechanisms involved in inflammation, differentiation, proliferation, and apoptosis. When physically mixed or covalently conjugated with cytotoxic agents, bacterial DNA or antigens, polymers can drastically alter specific genetically controlled responses to these agents (Kabanov, 2006). These effects, in part, result from cooperative interactions of polymers and nanomaterials with plasma cell membranes and trafficking of polymers and nanomaterials to intracellular organelles. Cells and whole organism responses to these materials can be phenotype or genotype dependent. In selected cases, polymer agents can bypass limitations to biological responses imposed by the genotype, for example, phenotypic correction of immune response by polyelectrolytes. Overall, these effects are relatively benign as they do not result in cytotoxicity or major toxicities in the body. Collectively, however, these studies support the need for thoroughly assessing pharmacogenomic effects of polymer materials to maximize clinical outcomes and understand the pharmacological and toxicological effects of polymer formulations of biological agents, i.e. polymer genomics. In addition, it is well described in the literature that cationic nanoparticles disrupt lipid bilayers (Hong *et al.*, 2006; Leroueil *et al.*, 2008), induce oxidative stress inside the cell as a result of cell-type interplay and cause in some cases acute lung inflammation when administered intratracheally (Tan and Huang, 2002; Beyerle *et al.*, 2010b; Beyerle *et al*., 2011a and Beyerle *et al*., 2011c). Intensive efforts will have to focus on the issue of cytotoxicity to obtain more insight in the exact mechanisms behind, which are multidimensional and largely depend on the application route as well as the formulation that is delivered. Therefore, tissue specific toxicity profiles are still needed and represent a great implement in improving non-viral delivery systems.
