The role of the cell surface glycocalyx in drug delivery to and through the endothelium

Cell membranes are key interfaces where materials engineering meets biology. Traditionally regarded as just the location of receptors regulating the uptake of molecules, we now know that all mammalian cell membranes are 'sugar coated'. These sugars, or glycans, form a matrix bound at the cell membrane via proteins and lipids, referred to as the glycocalyx, which modulate access to cell membrane receptors crucial for interactions with drug delivery systems (DDS). Focusing on the key blood-tissue barrier faced by most DDS to enable transport from the place of administration to target sites via the circulation, we critically assess the design of carriers for interactions at the endothelial cell surface. We also discuss the current challenges for this area and provide opportunities for future research efforts to more fully engineer DDS for controlled, efficient, and targeted interactions with the endothelium for therapeutic application.