Multifunctional Immunomodulating Polymer Conjugates for Targeting and Treating Glycocalyx Dysfunction in Inflammatory Conditions

炎症和免疫介导的疾病，如移植器官的排斥反应、涉及心脏或血管的疾病（心血管疾病）或自身免疫性疾病（如糖尿病或多发性硬化症）占全世界死亡人数的五分之三。内皮是控制炎症和免疫介导疾病的核心，因为它排列着脉管系统，标志着血液和所有器官之间的第一个接触点。内皮细胞的表面覆盖着糖萼，字面意思是“糖衣”，这是蛋白质和糖聚合物的网状结构，标志着血液和器官组织之间的界面。因此，健康的糖萼代表了抵抗炎症和免疫介导疾病的保护前线，而糖萼脱落被发现与疾病的严重程度和死亡率相关。因此，我们的目标是通过一种新的细胞表面工程方法快速重建糖萼功能，从而靶向和治疗糖萼功能障碍，使器官能够维持或重建其功能。为此，我们计划开发含有糖萼靶向和免疫调节功能的聚合物偶联物。缀合物应该能够选择性地结合并保留在内皮细胞表面，并且它们将呈现类似于天然糖萼层的糖部分。我们期望实现一种具有显著治疗潜力的新方法，以改善糖萼功能障碍导致病理的炎症性疾病的治疗。

Inflammatory and immune-mediated diseases, such as the rejection of transplanted organs, diseases involving the heart or blood vessels (cardiovascular diseases), or autoimmune diseases (e.g. diabetes or multiple sclerosis) account for 3 out 5 deaths worldwide. The endothelium is central to controlling inflammation and immune-mediated diseases since it lines the vasculature and marks the first point of contact between blood and all organs. The surface of the endothelial cells is covered by the glycocalyx, literally meaning “sugar coat”, which is a mesh-like structure of proteins and sugar polymers, marking the interface between bloodstream and organ tissue. Thus, a healthy glycocalyx represents the protective front line against inflammatory and immune-mediated diseases whereas glycocalyx shedding was found to correlate with disease severity and mortality. Therefore, we aim to target and treat glycocalyx dysfunction by rapidly rebuilding it through a new cell surface engineering approach, which should enable organs to maintain or reestablish their function. To do so, we are planning to develop polymer conjugates containing both glycocalyx targeting and immunomodulating functionalities. The conjugates should be able to selectively bind and retain on the endothelial cell surface and they will present sugar moieties which resemble the natural glycocalyx layer. We anticipate realizing a novel approach with significant therapeutic potential to improve treatment for inflammatory conditions where glycocalyx dysfunction is contributing to the pathology.