Nucleolipoplexes: A new paradigm for phospholipid bilayer-nucleic acid interactions

Most of the current research on synthetic bilayer membrane-nucleic acid complexes (lipoplexes) is addressed to lipid self-assemblies as nonviral vectors for genetic material. The vast majority of synthetic nonviral vectors so far considered consists of cationic lipid assemblies where DNA binds to cationic liposomes, thanks to charge compensation between the negative polyelectrolyte and the headgroups of the cationic lipid assembly. We report a SAXS investigation with the first evidence of formation of an ordered lamellar phase of the type L alpha c without any mediation from divalent cations or the presence of cationic lipids, where the complementary polynucleoticle strands spontaneously order in between a lamellar fluid phase formed by the anionic 1-palmitoyl-2-oleoylphosphatidyl-adenosine nucleolipid, POPA. This nucleolipid has full biological compatibility and can be enzymatically cleaved by phospholipases once in living organisms. While for conventional lipoplexes the driving force leading to condensation is clearly of electrostatic nature, in this case the absence of divalent cations and the presence of like charges on membranes and on the polyelectrolyte excludes this aspecific contribution. Spectroscopic observations (FTIR and UV) performed on the same complex highlighted the presence of molecular recognition interactions between the bases decorating the anionic bilayer and the complementary bases on the strands of the polynucleoticle. The fact that molecular recognition can be the driving force for bioconjugate constructs establishes a new paradigm with potentially important impact both in a biomedical field and in supramolecular chemistry.