Indocyanine green (ICG) is a fluorescent probe used in various optically mediated diagnostic and therapeutic applications. However, utility of ICG remains limited by its unstable optical properties and nonspecific localization. We have encapsulated ICG within electrostatically assembled mesocapsules (MCs) to explore its potential for targeted optical imaging and therapy. In this study, we investigate how the surface coating and size of the MCs influences ICG's biodistribution in vivo. ICG was administered intravenously to Swiss Webster mice as a free solution or encapsulated within either 100 nm diameter MCs coated with dextran; 500 nm diameter MCs coated with dextran; or 100 nm diameter MCs coated with 10 nm ferromagnetic iron oxide nanoparticles, themselves coated with polyethylene glycol. ICG was extracted from harvested blood and organs at various times and its amount quantified with fluorescence measurements. MCs containing ICG accumulated in organs of the reticuloendothelial system, namely, the liver and spleen, as well as the lungs. The circulation kinetics of ICG appeared unaffected by encapsulation; however, the deposition within organs other than the liver suggests a different biodistribution mechanism. Results suggest that the capsules' coating influences their biodistribution to a greater extent than their size. The MC encapsulation system allows for delivery of ICG to organs other than the liver, enabling the potential development of new optical imaging and therapeutic strategies.