Abstract:
Exploring chemistry at the cell surface through cell surface engineering (CSE) is a powerful tool for manipulating cell-cell interactions. This strategy is especially effective in controlling the immune response as immune cells function by ‘reading’ proteins and carbohydrates on the cell surface to identify cells as ‘safe’ or ‘harmful’. Here, we explore using CSE as a strategy to promote localized immunosuppression during organ transplantation. We specifically target the endothelial glycocalyx, a naturally occurring immunoregulatory structure that coats the inner surface of blood vessels. During organ procurement, the glycocalyx breaks down and the immunoprotective function of the glycocalyx is lost. We designed a series of biomimetic glycopolymers to generate a synthetic glycocalyx replacement on the endothelial cell surface that re-engineers the identity of the cells from ‘harmful’ to ‘safe’. A novel enzyme-mediated polymer attachment strategy was used to rapidly and selectively attach polymers in a chemically complex biological environment. The grafted polymers were able to recapitulate the natural immunosuppressive function of the glycocalyx by combining sterically driven immunocamouflage against immune cell binding with immune cell deactivation using carbohydrate based inhibitors. As a result, the polymer coating served as a potent immunosuppressant both in cell culture and in vivo, as demonstrated in an arterial transplant mouse model.