Nuclear import of polypeptides, polynucleotides and supramolecular complexes

Nuclear import of macromolecules or particles is a strictly regulated phenomenon that is now understood in some depth at the molecular level. Transport across nuclear membranes is controlled by nuclear pores, with the involvement of cytoplasmic receptors and accessory molecules. Each nuclear pore complex is an assembly of multiple copies of at least 30 distinct proteins, with a total mass of approximately 10(7) kDa. Passive transport of small molecules through nuclear pores is unrestricted, but efficient uptake of macromolecules requires nuclear localization signals, which facilitate the interaction with cytoplasmic receptor proteins. The basic architecture of the nuclear pore and the mechanisms that regulate nuclear import are summarized, in relation to import of endogenous molecules and viruses. Subsequently, the significance of these mechanisms in controlling gene delivery is discussed. Access of DNA to the nucleus is a major barrier to the success of gene therapy, although viruses have evolved mechanisms to exploit the active transport machinery within the host cell. A key step in the future development of non-viral gene therapy will be the design and development of synthetic systems for active delivery of DNA to the nucleus.