“Sweet” Architecture-Dependent Uptake of Glycocalyx-Mimicking Nanoparticles Based on Biodegradable Aliphatic Polyesters by Macrophages

Glyconanoparticles made by self-assembled glycopolymers currently are practical and efficient mimics of the glycocalyx on cell surfaces. Considering the complexity of the glycocalyx, glyconanoparticles with different sugars on their coronas, i.e., mixed-shell glycomicelles, could be more valuable compared to homoshell micelles. In this paper, we explore the architectural effect of the glyconanoparticle corona on glyconanoparticle macrophage endocytosis and lectin-binding ability. A series of glyconanoparticles composed of a biodegradable polyester backbone functionalized with galactoside or mannoside pendants were designed and prepared. The different architectures explored were single-component (galactoside or mannoside) coronas, homogeneously mixed coronas (MG) made by galactoside–mannoside copolymer chains, and blend-mixed coronas (M/G) constructed from two homoglycopolymers. Nanoparticles with a mixed shell showed a higher efficiency in cellular uptake and lectin-binding than those with a single sugar component. Meanwhile, unexpectedly, MG presented a significantly higher efficiency than M/G, although they had the same particle size and ratio of mannoside to galactoside. We attributed this apparent architectural effect to the difference in the phase behavior between MG and M/G; i.e., the former having a homogeneous corona allowed more sugar–receptor interactions in the contact region, while the latter having phase separation limited the simultaneous interaction of the two kinds of sugar units with the cell receptors.