We have engineered nano-sized constructs from erythrocytes doped with the FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG). Herein, we present results that demonstrate membrane cholesterol enrichment is associated with reduced uptake of these nanoparticles by macrophages in vitro, and greater accumulation of the nanoparticles in intraperitoneal implants in immunodeficient mice. These preliminary findings suggest that cholesterol-enrichment of erythrocyte-derived optical nanoparticles can provide a potential capability for enhanced NIR imaging of tumors. © 2021 SPIE. All rights reserved.