High-Density Lipoproteins: Nature’s Multifunctional Nanoparticles

High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well-known as the “good” cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and antioxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, and inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultrasmall size (8–12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12–24 h), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to those of endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize (a) clinical pharmacokinetics and safety of reconstituted HDL products, (b) comparison of HDL with inorganic and other organic nanoparticles, (c) the rationale for using HDL as drug delivery vehicles for important therapeutic indications, (d) the current state-of-the-art in HDL production, and (e) HDL-based drug delivery strategies for small molecules, peptides/proteins, nucleic acids, and imaging agents targeted to various organs.