Lipid and hydrophobic modification of cationic carriers on route to superior gene vectors

Gene therapy has been pursued in the past two decades for treatment of diseases associated with defective gene expression. The insertion of a therapeutic gene into cells, followed by its expression, and consequently the inhibition or activation of target proteins constitute the general steps for a beneficial outcome in such an approach. However, the future of this approach will rely upon safe and effective gene carriers. Cationic polymers represent a class of non-viral carriers that can be optimally engineered to facilitate gene delivery to target cells and amphiphilic polymers have been particularly appealing due to delicate balance of physical properties that might optimize their functional performance. This review was complied with a focus on recent progress on lipid and hydrophobically modified polymers, and aims to provide new insights into development of this type of gene carriers. In particular, we will focus on the insertion of lipid or hydrophobic moieties into cationic carriers and its influence on the gene delivery performance. Critical parameters influencing the condensation of nucleic acids, surface properties and aggregation behavior of polyplexes, and the ability of the carrier-cargo complexes to dissociate will be described, all in the context of in vitro and in vivo performance of the carriers.