Checkpoint‐Directed Glycoengineering Reprograms the Vascular Lumen for Siglec‐Mediated Immune Regulation

Dysregulated immune activation at the vascular surface drives microvascular inflammation and tissue injury in many diseases, yet current therapies do not restore immune regulation at the blood‐vessel interface. Terminal sialic acids engage inhibitory Siglec receptors on circulating immune cells and function as endogenous glyco‐immune checkpoint ligands. Loss of sialylation on vascular endothelial cells during injury disrupts this regulatory axis and promotes vascular damage. Here, we introduce a checkpoint‐directed glycoengineering strategy that installs multivalent Siglec‐engaging sialic acid ligands on a macromolecular scaffold at the vascular interface to reprogram Siglec‐mediated immune regulation. Covalent anchoring of Siglec‐engaging conjugates to the vascular surface suppressed leukocyte‐mediated cytotoxicity, inflammatory cytokine production, adhesion molecule accessibility, and complement deposition. Protection was dose‐dependent and required selective sialic acid–Siglec‐7/‐9 engagement, as demonstrated by enzymatic desialylation, Siglec‐Fc binding, and receptor blockade. In vascular allografts, this Siglec‐engaging modification preserved endothelial integrity and suppressed innate and adaptive immune activation, neutrophil recruitment, dendritic‐cell activation, and T‐cell infiltration. In an allogeneic rat kidney transplant model, this approach attenuated microvascular inflammation, complement deposition, and tissue injury, resulting in vascular protection and demonstrating the power of glycan reprogramming. These findings establish Siglec‐directed immune‐glycoengineering as a mechanistically defined local checkpoint strategy that reprograms the vasculature into an active immunoregulatory interface.