Evolution of cross-linked non-viral gene delivery systems

Developing a non-viral gene delivery system that functions in vivo raises the challenge of finding solutions to efficiently deliver DNA to the cell surface that are also compatible with the efficient release of DNA into the cytosol. The stability, particle size and charge of DNA polyplexes and lipoplexes may be optimized to mediate efficient in vitro transfection only to find that different properties are necessary for successful in vivo transfection. Despite their versatility and improved safety, non-viral gene vectors still lack appreciable in vivo transfection efficiency compared to viral vectors. An emerging theme in recent studies is the use of cross-linking to achieve balance between the stability of polyplexes and lipoplexes in the blood and the controlled release of DNA in the cytosol. This review evaluates the evolution of cross-linking strategies aimed at transiently stabilizing non-viral gene delivery systems.