The efficiency of nanoparticle-based drug delivery systems to accumulate in targeted tumor sites is low owing primarily to the various biological mechanisms that promote premature clearance, such as renal filtration or the mononuclear phagocyte system (MPS). Such obstacles to enhanced tumor accumulation of nanomedicines remain formidable challenges to drug carrier design. It is thought that nanoparticles decorated with bioactive groups such as glycopolymers, compared to individual monovalent carbohydrate ligands, can assist in the enhanced delivery of payloads to tumors due to their multivalent effect. While glycopolymers are widely applied, limited attention has been dedicated to understanding how the presentation of glycopolymers on the surface of micelle may affect the biological activity. We utilized biodegradable and biocompatible polylactide–fructose block copolymers to investigate the effect of chain length of the hydrophilic fructose block on the biological activity. Three different fructose chain length polymers were prepared and self-assembled into spherical micelles. We discovered that their bioactivity is sugar-length-dependent, where a minimum sugar length is required to enhance cellular uptake and bind to receptors on the cell surface. According to SAXS (small angle X-ray scattering) data, micelles were formed in three layers with a polylactide core, followed by a mixed layer which may contains both PLA and fructose and finally an outer layer of fructose. The level of hydration was observed to be dependent on the length of the polymer with longer polymers leading to more hydrated glycopolymer layers. As a result, the high water content promoted enhanced flexibility of the fructose segments coinciding with effective receptor binding. This led to enhanced cell uptake by MDA-MB-231 and MCF-7 cells, which overexpress GLUT5 receptors, which ultimately resulted in higher accumulation in multicellular spheroid (3D) models. Moreover, the longer fructose chain length micelles exhibited reduced clearance by MPS in an in vivo study.