Tuning the Composition of Spherical High-Density Lipoprotein-Like Nanoparticles Modulates in Vitro Function

High-density lipoprotein (HDL) cholesterol (HDL-C) levels have been associated with risk of atherosclerotic cardiovascular disease (ASCVD). Therapeutic interventions aimed at increasing HDL-C have largely failed to produce patient benefits in clinical trials. Thus, there has been a shift away from targeting HDL-C and a focus on better understanding HDL structure–function relationships. Because of the heterogeneity of natural HDLs, HDL mimetics with defined physicochemical properties provide a useful tool to study HDL function(s). Here, we report the design and in vitro characterization of spherical HDL-like nanoparticles (HDL NPs) incorporating organic core (oc) scaffolds to investigate how core composition and phospholipids influence HDL NP function. We synthesized six unique spherical oc-HDL NPs and confirmed the formation of nanoparticles ∼10–15 nm in diameter and with physical features consistent with native HDL. We identified an oc-HDL NP that exhibited superior cholesterol efflux capacity and anti-inflammatory function, providing insights into engineering HDL mimetics as effective therapies.