Localized, non-viral delivery of nucleic acids: Opportunities, challenges and current strategies

Localized delivery of drugs is an emerging field both with regards to drug delivery during disease as well as in tissue engineering. Despite significant achievements made in the last decades, the efficient delivery of proteins and peptides remains challenging, especially in cases requiring long-term release of proteins after application. The localized delivery of nucleic acids (NA) represents an interesting alternative due to higher physicochemical stability of NA, increased efficiency by harnessing cells as bioreactors for the production of required proteins and improved versatility with regards to expression of specific proteins through plasmid DNA or repression of gene products through siRNA. However, unlike most proteins and peptides, NA must be delivered to the cytoplasm or nucleus to be efficacious, resulting in significant delivery challenges. We herein describe frequently used non-viral vectors for the delivery of NA including polyplexes, lipoplexes and lipopolyplexes and summarize recent developments in the field of nucleic acid delivery systems for local application based on hydrogels, solid scaffolds and physical delivery methods. The challenges associated with the different approaches are identified and options to address these challenges are discussed.