"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.