Engineering a New Lipid-Based Platform for the Delivery of Hydrophobic Drugs

Abstract

Hydrophobic small molecules account for an estimated 70–90% of drug candidates in development, yet their delivery remains fundamentally limited by the bilayer-based carriers that dominate the field, which confine lipophilic cargo to a structured membrane shell that is both chemically mismatched and geometrically constrained. Here, we describe artificial lipid droplets, nanoparticles inspired by the cellular organelles cells use to store and mobilize hydrophobic lipids, comprising a liquid triacylglycerol core stabilized by a fluid phospholipid monolayer, as a structurally distinct platform for hydrophobic drug delivery. Artificial lipid droplets encapsulate paclitaxel at 85–95% e!ciency across a 40-fold concentration range with no evidence of saturation, remain colloidally stable over 35 days, and deliver five-fold greater intracellular drug accumulation than liposomal controls at equivalent particle dose. These findings establish artificial lipid droplets as a physically motivated and experimentally validated platform for the delivery of poorly water-soluble therapeutics.