Targeting C-type lectin receptors with multivalent carbohydrate ligands.

C-type lectin receptors (CLRs) represent a large receptor family including collectins, selectins, lymphocyte lectins, and proteoglycans. CLRs share a structurally homologous carbohydrate-recognition domain (CRD) and often bind carbohydrates in a Ca²⁺-dependent manner. In innate immunity, CLRs serve as pattern recognition receptors (PRRs) and bind to the glycan structures of pathogens and also to self-antigens. In nature, the low affinity of CLR/carbohydrate interactions is overcome by multivalent ligand presentation at the surface of cells or pathogens. Thus, multivalency is a promising strategy for targeting CLR-expressing cells and, indeed, carbohydrate-based targeting approaches have been employed for a number of CLRs, including asialoglycoprotein receptor (ASGPR) in the liver, or DC-SIGN expressed by dendritic cells. Since CLR engagement not only mediates endocytosis but also influences intracellular signaling pathways, CLR targeting may allow for cell-specific drug delivery and also the modulation of cellular functions. Glyconanoparticles, glycodendrimers, and glycoliposomes were successfully used as tools for CLR-specific targeting. This review will discuss different approaches for multivalent CLR ligand presentation and aims to highlight how CLR targeting has been employed for cell specific drug delivery. Major emphasis is directed towards targeting of CLRs expressed by antigen-presenting cells to modulate immune responses.