Abstract
DNA delivery holds great therapeutic potential, but several barriers have frustrated many creative approaches over the last decade. The presence of an established antiviral immunity in many patients and the rapid induction of an adaptive immune response in naive patients continues to block many attempts to introduce DNA by viral vectors. Nonviral delivery strategies avoid the problems of viral-coat proteins, but encountered new challenges of low and transient expression related to physiological and innate immune barriers. Naked DNA must overcome serum nucleases, conserved immune receptors, nonspecific clearance, cellular membrane barriers, endosomal degradation, and intracellular trafficking to ensure optimal localization and expression (Fig. 1). This chapter reviews the obstacles to nonviral DNA delivery and highlights current formulation strategies designed to ensure efficient localization and expression of therapeutic genes.
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