In Situ Bioorthogonal Repair of the Vascular Endothelium Glycocalyx to Treat Acute Lung Injury

Abstract In acute lung injury, destruction of the lung endothelial glycocalyx leads to vessel permeabilization and contributes to pulmonary edema and inflammation. Heparan sulfate, which accounts for >70% of glycosaminoglycans in the endothelial glycocalyx, plays a crucial physiological anti‐inflammatory role. To treat acute lung injury, it is explored whether a two‐step in vivo bioorthogonal chemistry strategy can covalently link intravenously administered heparan sulfate to the lung vascular endothelium and the damaged glycocalyx. First, fusogenic liposomes (EBP‐Tz‐FLs) carrying the reactive group tetrazine (Tz), and an E‐selectin‐binding peptide (EBP) to target the lung inflammatory endothelium are administered intravenously. This step aimed to anchor the tetrazine group to the membrane of inflammatory endothelial cells. Second, heparan sulfate (HS‐TCO) conjugated to the trans ‐cyclooctene (TCO) group, which spontaneously reacts with Tz, is injected intravenously, leading to covalent heparan sulfate addition to the vascular endothelium. In a mouse model of acute lung injury, this approach substantially reduced vascular permeability and attenuated lung tissue infiltration. The EBP‐Tz‐FLs and HS‐TCO showed favorable biocompatibility and safety both in vitro and in vivo. The proposed strategy shows good promise in acute lung injury therapy and covalently anchoring functional molecules onto the membrane of target cells.