Riding a Vascular Time Train to Spatiotemporally Attenuate Thrombosis and Restenosis by Double Presentation of Therapeutic Gas and Biomacromolecules

Abstract

Endothelial injury is a common occurrence following stent implantation, often leading to complications such as restenosis and thrombosis. To address this issue, we have developed a multi-functional stent coating that combines a dopamine-copper (DA-Cu) base with therapeutic biomolecule modification, including nitric oxide (NO) precursor L-arginine, endothelial glycocalyx heparin, and endothelial cell (EC) catcher vascular endothelial growth factor (VEGF). In our stent coating, the incorporated Cu acts as a sustainable catalyst for converting endogenous NO donors into NO, and the immobilized arginine serves as a precursor for NO generation under the effect of endothelial nitric oxide synthase (eNOS). The presence of heparin endows the stent coating with anticoagulant ability and enhances eNOS activity, whilst rapid capture of EC by VEGF accelerates re-endothelialization. After in vivo implantation, the antioxidant elements and produced NO alleviate the inflammatory response, establishing a favorable healing environment. The conjugated VEGF contributes to the formation of a new and intact endothelium on the stent surface to counteract inappropriate vascular cell behaviors. The long-lasting NO flux inhibits smooth muscle cell (SMC) migration and prevents its excessive proliferation, reducing the risk of endothelial hyperplasia. This innovative coating enables the dual delivery of VEGF and NO to target procedural vascular repair phases: promoting rapid re-endothelialization, effectively preventing thrombosis, and suppressing inflammation and restenosis. Ultimately, this innovative coating has the potential to improve therapeutic outcomes following stent implantation.