Engineered Silyl Lipids to Modulate Liposome and Lipid Nanoparticle Properties for mRNA Delivery

The design of amphiphilic lipid structures can be used to modulate key properties for diverse applications in biology and nanomaterials. We have engineered a structurally diverse class of amphiphilic silyl lipids using a hydrosilylation reaction as the key step to access lipids that vary the silyldimethyl position, branching, length, and substituents in the lipid tail. We demonstrate that the size, zeta potential, rRNA encapsulation, stability, bilayer fluidity, and mRNA transfection are controlled by varying the structure of the silyl lipid tail. Five silyl lipids exhibit high encapsulation, and three feature enhanced stability and transfection in HEK293T cells relative to DOTAP as a classic reference lipid. Incorporation of a branching silyldimethyl group (in place of a <i>cis</i> alkene or methylene) increases bilayer fluidity in liposomes.These results support the idea that incorporating a silyldimethyl group and accessing diverse lipid structures can control liposome properties and mRNA delivery, showing promise for using silyl lipid structures in other biology and biomaterial applications.