Lipid-based micelles provide an attractive option for therapeutic and diagnostic applications because of their small size (<20 nm) and ability to self-assemble and improve the solubility of both hydrophobic drugs and dyes. Their use, however, has been challenged by the fact that these particles are inherently unstable in serum becaue of interactions with protein components, which drives the micelle equilibrium to the monomeric state. We have engineered serum stabilized micelles using short quadruplex forming oligonucleotide extensions as the lipid headgroup. Quadruplex formation on the surface of the particles, confirmed by H-1 NMR, results in slight distortion of the otherwise spherical micelles and renders them resistant to disassembly by serum proteins for >24 h. Using antisense oligonucleotides we demonstrated that disruption of the quadruplex leads to micelle destabilization and cargo release. The ability to use oligonucleotide interactions to control lipid particle stability represents a new approach in the design of programmed nanoscale devices.