The use of surface-based methods for the delivery of therapeutics has recently generated increasing interest. These platforms have tremendous potential to minimize detrimental side effects associated with systemic delivery by localizing the therapeutic vehicle, and thus provide higher local doses for improved efficacy. Cationic lipids are one of the most commonly used synthetic carriers for the delivery of genetic cargo, such as DNA and RNA. However, reports on the use of lipid-based films for gene delivery are scarce. Here we investigate the use of a lipid-based film for the in vitro delivery of plasmid DNA. Solid DNA-lipid films show very low levels of transfection, while identical complexes prepared for bolus delivery provide high levels of transfection when used directly. We investigate the mechanism, whereby the activity of these solid-state films is lost and suggest methods for circumventing these challenges and restoring the efficacy of these films as gene delivery platforms. (c) 2013 American Institute of Chemical Engineers AIChE J, 59: 3203-3213, 2013