Structure and kinetics of lipid-nucleic acid complexes

Nily Dan*, Dganit Danino

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

46 Scopus citations

Abstract

The structure and function of lipid-based complexes (lipoplexes) have been widely investigated as cellular delivery vehicles for nucleic acids - DNA and siRNA. Transfection efficiency in applications such as gene therapy and gene silencing has been clearly linked to the local, nano-scale organization of the nucleic acid in the vehicle, as well as to the global properties (e.g. size) of the carriers. This review focuses on both the structure of DNA and siRNA complexes with cationic lipids, and the kinetics of structure evolution during complex formation. The local organization of the lipoplexes is largely set by thermodynamic, equilibrium forces, dominated by the lipid preferred phase. As a result, complexation of linear lambda-phage DNA, circular plasmid DNA, or siRNA with lamellae-favoring lipids (or lipid mixtures) forms multi-lamellar L αC liquid crystalline arrays. Complexes created with lipids that have bulky tail groups may form inverted hexagonal H IIC phases, or bicontinuous cubic QII C phases. The kinetics of complex formation dominates the large-scale, global structure and the properties of lipoplexes. Furthermore, the time-scales required for the evolution of the equilibrium structure may be much longer than expected. In general, the process may be divided into three distinct stages: An initial binding, or adsorption step, where the nucleic acid binds onto the surface of the cationic vesicles. This step is relatively rapid, occurring on time scales of order of milliseconds, and largely insensitive to system parameters. In the second step, vesicles carrying adsorbed nucleic acid aggregate to form larger complexes. This step is sensitive to the lipid characteristics, in particular the bilayer rigidity and propensity to rupture, and to the lipid to nucleic acid (L/D) charge ratio, and is characterized by time scales of order seconds. The last and final step is that of internal rearrangement, where the overall global structure remains constant while local adjustment of the nucleic acid/lipid organization takes place. This step may occur on unusually long time scales of order hours or longer. This rate, as well, is highly sensitive to lipid characteristics, including membrane fluidity and rigidity. While the three step process is consistent with many experimental observations to date, improving the performance of these non-viral vectors requires better understanding of the correlations between the parameters that influence lipoplexes' formation and stability and the specific rate constants i.e., the timescales required to obtain the equilibrium structures. Moreover, new types of cellular delivery agents are now emerging, such as antimicrobial peptide complexes with anionic lipids, and other proteins and small-molecule lipid carriers, suggesting that better understanding of lipoplex kinetics would apply to a variety of new systems in biotechnology and nanomedicine.

Original languageEnglish
Pages (from-to)230-239
Number of pages10
JournalAdvances in Colloid and Interface Science
Volume205
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • Cryo-TEM
  • DNA/lipid
  • Gene therapy
  • Kinetics
  • Lipoplexes
  • Non-viral carriers
  • siRNA

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