Polyelectrolyte Complexes : Linking Chemistry and Structure to Biological Function

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Polyelectrolyte complexes are nanoparticles that form via electrostatic attraction between a polycation and polyanion. A particular class of these systems is used to introduce genetic material into cells when the polyanion is a nucleic acid sequence like DNA or RNA. We have studied these delivery systems using the polycation chitosan, a natural polymer of glucosamine that is partly acetylated, and plasmid DNA to express genes when delivered to the nucleus. We have also developed nanoparticles containing siRNA which stop expression of the target gene. Certain mechanisms by which these systems function efficiently have been elucidated using a family of custom-produced chitosans and a battery of physicochemical and structural characterization methods of the polymers and resulting nanostructures, in addition to assessment of cell uptake, intracellular trafficking and transgene expression in several cell types. This proposal aims to further elucidate the fundamental mechanisms by which effective and non-toxic delivery of nucleic acids into cells can be achieved. The overall objective is to provide design principles and elucidate mechanisms of biological function for efficient and non-toxic chitosan/nucleic acid delivery vehicles for gene expression/knockdown, recombinant protein production and in vivo applications in animals and humans. A vast number of studies are performed worldwide on nanoparticle systems for the intracellular delivery of nucleic acids generating increased knowledge of their function and biological effects. Nonetheless many studies are descriptive with only a minority revealing basic mechanisms that can be used to identify further systems which can be effective and safe. This proposal aims to extend our recent work where basic principles relating chemical and structural properties of polyelectrolyte complexes to their ability to effectively deliver nucleic acids to intracellular sites of action will be advanced. The results will be significant for the fields of nanotechnology and cell biology.