Unveiling the Interaction Mechanism of siRNA with Lipid Bilayers of Different Types for siRNA-Based Therapy

siRNA-based therapy is a new approach for the treatment of diseases, including cancer, viral infections, and so forth. When liposomes serve as an effective siRNA carrier, unveiling the siRNA-liposome interaction mechanism becomes extremely significant for siRNA-based therapy. Here, we investigate the interactions between siRNA and liposomes with different types of lipid molecules and find that the stable adsorption of siRNA on the phosphoethanolamine (PE) bilayer liposome mainly relies on hydrogen bonding between the siRNA phosphate groups and the ethanolamine structure of PE lipid molecules. On the contrary, the stability of the adsorption of siRNA on the phosphorylcholine (PC) bilayer liposome is often determined by electrostatic interactions, and the adsorption stability can be modulated by calcium ions. The concept of "bridging" is also invoked to reveal the adsorption mechanism of siRNA on the lipid bilayer after adding calcium ions. We found that adding divalent calcium ions can better regulate the stability of siRNA adsorption on the PC lipid bilayer, but calcium ions cannot regulate the adsorption of siRNA on the PE lipid bilayer, which is determined by H-bonds. In short, this work reveals the different adsorption mechanisms of siRNA on liposomes, which provides a physical insight into siRNA-based therapy at the molecular level.