Liposomes Derived From Macrocyclic Polyamine As A Versatile Macromolecule Delivery System

Macromolecular therapeutic agents such as nucleic acids and proteins have attracted increased attention due to the satisfactory specificity and potent therapeutic effect, holding great significance for the treatment of major and complicated diseases. Cationic lipids possess tremendous potential for the intercellular delivery of macromolecular agents, while their delivery efficiency and biocompatibility remain challenging. Herein, two 1,4,7,10-tetraazacyclododecane (cyden)-based lipids and their Zn(II) complexes were prepared, and the formed liposomes were applied as versatile vectors for various macromolecular cargos including plasmid DNA, siRNA, and proteins. It was found that high delivery efficiency toward different types of cargos could be achieved by simple adjustment of the lipid structure. Zn coordination could largely reduce the cytotoxicity of the delivery complexes, and the Zn(II)-coordinated single-tailed cyclen lipid exhibited much higher plasmid gene transfection efficiency than Lipofectamine 2000. Meanwhile, cyclen lipids with double fluorinated tails could give better performance in the delivery of siRNA. It was supposed that lipids with a relatively lower nucleic acid condensation ability might release the cargo more easily in the cytoplasm, resulting in weaker DNA transfection and better siRNA gene silencing. Moreover, the double-tailed lipid could also efficiently transfer special proteins into cells without function loss. These results show the promise of cyden-based lipids in the application of nucleic acid and protein delivery and further biomacromolecule therapy.