The study of lipoproteins, natural nanoparticles comprised of lipids and apolipoproteins that transport fats throughout the body, is of key importance to better understand, treat, and prevent cardiovascular disease. In the current study, we have developed a lipoprotein-based nanoparticle that consists of a quantum dot (QD) core and Cy5.5 labeled lipidic coating. The methodology allows judicious tuning of the QD/Cy5.5 ratio, which enabled us to optimize Förster resonance energy transfer (FRET) between the QD core and the Cy5.5-labeled coating. This phenomenon allowed us to study lipoprotein-lipoprotein interactions, lipid exchange dynamics, and the influence of apolipoproteins on these processes. Moreover, we were able to study HDL-cell interactions and exploit FRET to visualize HDL association with live macrophage cells.