This paper illustrates how principles of colloid science are useful in studying atherosclerosis. Accumulation of foam cells in the arterial intima is a key step in atherogenesis. The extent of foam cell formation is enhanced by low density lipoprotein (LDL) aggregates, and we have previously shown that the size of sphingomyelinase (Smase)-hydrolysis-induced aggregates depends directly on the concentration of ceramide generated in the LDL phospholipid monolayer, mediated by the hydrophobic effect. Here, we focus on the effect of LDL aggregate particle sizes on their subsequent uptake by macrophages. Our data show the first direct measurement of uptake as a function of aggregate size and the first direct comparison of uptake after Smase-catalyzed and vortex-mixing-mediated aggregation. Vortex-mixed aggregates with radii 20-77 nm showed maximal uptake similar to 118 mu g sterol/mg protein at a 53 nm intermediate size, consistent with a mathematical model describing competition between aggregate surface area and volume. Smase-treated aggregates with radii 25-211 nm also showed maximal uptake at an intermediate size, similar to 58 mu g sterol/mg protein for 132 nm particles, and fit a modified model that incorporated ceramide concentration expressed as aggregate size. This study shows that particle size is significant and composition may also be a factor in LDL uptake. (C) 2010 Elsevier Inc. All rights reserved.