UC San Diego

The ability to systematically manipulate the glycocalyx, composed of the collection of glycoconjugates extending from the cell surface, is paramount to understanding structure-function relationships in glycan-mediated biological processes including cell signaling, development, and pathogenesis. Diverse approaches for glycan engineering have emerged, drawing upon chemical, chemoenzymatic, and genetic techniques to augment, edit, or remove cell surface glycoconjugates. Among these strategies, methods to build complexity at the cellular boundary de novo have been particularly effective in revealing the complex relationships between glycan organization within the glycocalyx and the exchange of information between a cell and its environment. While major strides have been made in glycocalyx engineering through the combination of genetic knockouts paired with synthetic glycomaterials that can be inserted into the glycocalyx, these methods generally lack specificity and dynamic control, limiting their biological applications. In this work, several cell surface engineering strategies are reported which collectively address these challenges. First, the ability to spatially program glycan binding activity at the cell surface by scaffolding an artificial glycocalyx comprising both distally presented glycopolymers and surface-proximal glycolipids is presented. Next, utilizing materials bearing photolabile membrane anchors, the ability to spatiotemporally pattern glycocalyx interactions is demonstrated in the context of the mucosal barrier. This glycocalyx photoengineering technique enabled study of the effects of lectin crosslinking on mucin shedding, a key process in pathogenesis. Next, glycomaterials composed of a targeting aptamer unit and bioactive glycodomain were used to program activity in a cell and developmental-stage specific manner in the context of stem cell differentiation, where enhanced differentiation outcomes were observed. Together, these precision glycocalyx engineering strategies enable selective activation or deactivation of glycan dependent interactions and may shed light on the roles of the glycocalyx in therapeutically relevant biological processes.