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. Impact statement This review summarizes how biomaterial substrate modifications (e.g. chemical modifications like natural coatings, ligands, or functional side groups, and/or physical modifications such as topography or stiffness) can prime the cellular response to nonviral gene delivery (e.g. affecting integrin binding and focal adhesion formation, cytoskeletal remodeling, endocytic mechanisms, and intracellular trafficking), to aid in improving gene delivery for applications where a cell-material interface might exist (e.g. tissue engineering scaffolds, medical implants and devices, sensors and diagnostics, wound dressings).
Biomaterial substrate modifications that influence cell-material interactions to prime cellular responses to nonviral gene delivery
