A Modular Approach Toward Controlling Stability of Oligonucleotide‐Stabilized Lipid Micelles

Lipid micelles represent an important class of nanoparticle with the potential to enhance the solubility and delivery of hydrophobic drugs and imaging agents. Their small size (<50 nm) makes them ideal candidates for both passive tumor uptake and deep tissue penetration. The use of lipid micelles as delivery vehicles, however, has been challenged by the fact that these particles are inherently unstable in vivo , particularly due to interactions of lipids with serum proteins. We have developed a modular platform in which lipid monomers modified with short 16‐base oligonucleotide sequences function to overcome the challenges associated with micelle‐based drug delivery. Oligonucleotide‐lipid conjugates are synthesized manually using standard phosphoramidite chemistry, and oligonucleotide‐stabilized lipid micelles (OLMs) are then assembled in aqueous media. Micelle stability is assessed in the presence of serum proteins using techniques including Förster resonance energy transfer (FRET). We present data in which we have systematically varied both lipid structure and oligonucleotide sequence to establish design rules to guide the assembly and stability of OLMs. The modularity of this approach provides a pathway toward the engineering of delivery vehicles with precisely defined structure, stability, and kinetic profiles.