Lipid droplet (LD) accumulation, a key feature of foam cells, constitutes an 
attractive target for therapeutic intervention in atherosclerosis. However, 
despite advances in cellular imaging techniques, current noninvasive and 
quantitative methods have limited application in living foam cells. Here, using 
optical diffraction tomography (ODT), we performed quantitative morphological 
and biophysical analysis of living foam cells in a label-free manner. We 
identified LDs in foam cells by verifying the specific refractive index using 
correlative imaging comprising ODT integrated with three-dimensional 
fluorescence imaging. Through time-lapse monitoring of three-dimensional 
dynamics of label-free living foam cells, we precisely and quantitatively 
evaluated the therapeutic effects of a nanodrug (mannose-polyethylene 
glycol-glycol chitosan-fluorescein isothiocyanate-lobeglitazone; MMR-Lobe) 
designed to affect the targeted delivery of lobeglitazone to foam cells based on 
high mannose receptor specificity. Furthermore, by exploiting 
machine-learning-based image analysis, we further demonstrated therapeutic 
evaluation at the single-cell level. These findings suggest that refractive 
index measurement is a promising tool to explore new drugs against LD-related 
metabolic diseases.