(9b) Matrix-Mediated Non-Viral Gene Delivery

Non-viral vectors used in gene therapy applications can be administered locally or systemically to stimulate exogenous gene expression in host cells. Extensive efforts have been made to synthesize vectors for plasmid DNA (pDNA) delivery in order to improve the uptake and expression of the delivered gene. Gene delivery is also mediated by the cellular microenvironment, the properties of which vary with tissue type. Previously, we have demonstrated that the stiffness of the cell adhesion matrix regulates cellular uptake of pDNA and expression of a reporter gene encoding luciferase [1]. In this study, we use a cell-adherent hydrogel, tuned to mimic the stiffness of various tissue types, to demonstrate that matrix mechanics regulate the cellular uptake and subsequent expression of pDNA encoding bone morphogenetic protein (BMP). In addition, we present the effects of cell type combined with matrix mechanics in regulating gene delivery as well as the underlying mechanism of these interactions. Overall, the results of this study may facilitate the development of gene delivery strategies and the design of scaffolds for gene-based tissue regeneration therapies.

[1] H.J. Kong, J. Liu, K. Riddle, T. Matsumoto, K. Leach, D.J. Mooney. Nature Materials 4, 460, 2005.