The present invention provides a non-naturally occurring High-Density Lipoprotein-like peptide-phospholipid scaffold (&ldquo；HPPS&rdquo；) nanoparticle. More particularly, the invention provides a non-naturally occurring peptide-lipid nanoscaffold comprising: (a) at least one phospholipid； (b) at least one unsaturated lipid, preferably an unsaturated sterol ester, further preferably an unsaturated cholesterol ester, further preferably cholsteryl oleate； and (c) at least one peptide, the peptide comprising an amino acid sequence capable of forming at least one amphipathic a-helix； wherein the components a), b) and c) associate to form the peptide-phospholipid nanoscaffold. In embodiments of the present invention, a cell surface receptor ligand is incorporated into the HPPS. In one embodiment, the cell surface receptor ligand is covalently bonded to the peptide scaffold of the HPPS nanoparticles. In other embodiments, a cell surface receptor ligand is coupled to a lipid anchor and is displayed on the surface of the HPPS nanoparticles by incorporation of the lipid anchor into the phospholipids monolayer of the HPPS nanoparticle. The present invention also provides pharmaceutical formulations comprising HPPS nanoparticles and methods of making the HPPS nanoparticles.
