Biological Systems Engineering


Date of this Version



2019 by the Society for Experimental Biology and Medicine


Experimental Biology and Medicine 2019; 244: 100–113. DOI: 10.1177/1535370218821060


Gene delivery is the transfer of exogenous genetic material into somatic cells to modify their gene expression, with applications including tissue engineering, regenerative medicine, sensors and diagnostics, and gene therapy. Viral vectors are considered the most effective system to deliver nucleic acids, yet safety concerns and many other disadvantages have resulted in investigations into an alternative option, i.e. nonviral gene delivery. Chemical nonviral gene delivery is typically accomplished by electrostatically complexing cationic lipids or polymers with negatively charged nucleic acids. Unfortunately, nonviral gene delivery suffers from low efficiency due to barriers that impede transfection success, including intracellular processes such as internalization, endosomal escape, cytosolic trafficking, and nuclear entry. Efforts to improve nonviral gene delivery have focused on modifying nonviral vectors, yet a novel solution that may prove more effective than vector modifications is stimulating or “priming” cells before transfection to modulate and mitigate the cellular response to nonviral gene delivery. In applications where a cell-material interface exists, cell priming can come from cues from the substrate, through chemical modifications such as the addition of natural coatings, ligands, or functional side groups, and/or physical modifications such as topography or stiffness, to mimic extracellular matrix cues and modulate cellular behaviors that influence transfection efficiency. This review summarizes how biomaterial substrate modifications can prime the cellular response to nonviral gene delivery (e.g. integrin binding and focal adhesion formation, cytoskeletal remodeling, endocytic mechanisms, intracellular trafficking) to aid in improving gene delivery for future therapeutic applications.