Unraveling the effects of siRNA carrier systems on cell physiology: a multiparametric approach demonstrated on dextran nanogels

Aim: The extent of cell-nanoparticle interactions between a polycationic siRNA nanocarrier system (dextran nanogels) and cultured cells was analyzed. Materials & methods: A multiparametric methodology is introduced to examine the cytotoxic effects of a model siRNA carrier (dextran nanogels) on different cell types, including primary human cells. Using this methodology, the nontoxic concentration of nanogels could be defined and the mechanisms contributing to their toxic profile were unraveled. Results: Above the toxicity threshold, nanogels were found to induce oxidative stress and destabilize the plasma membrane. Furthermore, nanogel-induced cellular stress led to DNA damage, impeded cell functionality and intracellular signaling, resulting in unspecific regulation of gene expression. Conclusion: This methodology shows that current toxicity assays such as the 3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide assay are not adequate to assess the full spectrum of cell-nanoparticle interactions and more in-depth studies are required. Original submitted 8 May 2012; Revised submitted 3 December 2012; Published online 12 June 2013