A sequentially orthogonal dual-peptide (TPS/DGEA) coating with synergistic anticoagulant, anti-inflammatory and...

Drug-eluting stents effectively reduce restenosis but are hampered by delayed re-endothelialization and chronic inflammation, which can trigger late thrombosis. Addressing this requires a surface that simultaneously promotes rapid endothelial repair, inhibits thrombosis, and modulates the local immune environment. Herein, we report a rationally designed dual-peptide coating on a titanium stent material, fabricated via a sequential orthogonal chemical coupling strategy. An antifouling polyethylene glycol (PEG) layer was first immobilized on a polydopamine base, followed by the controlled, stepwise grafting of the endothelial progenitor cell (EPC)-specific TPS peptide and the bifunctional DGEA peptide. This approach allows for precise tuning of the peptide ratio. The resulting TPS/DGEA coating demonstrated a temporal synergy in promoting endothelialization: the TPS moiety was responsible for the specific and efficient capture of EPCs, while the DGEA moiety subsequently enhanced the spreading and proliferation of both captured EPCs and mature endothelial cells, accelerating the formation of a confluent endothelium. Crucially, leveraging the intrinsic bifunctionality of the immobilized DGEA peptide, the coating significantly suppressed M1 macrophage polarization and reduced pro-inflammatory TNF-αsecretion, demonstrating potent immunomodulatory effects. Furthermore, the coating exhibited superior hemocompatibility through a dual-mechanism anticoagulation approach, combining the passive protein resistance of the PEG layer with the active molecular antagonism of the DGEA peptide against platelet integrinα₂β₁, which collectively inhibited platelet adhesion/activation and prolonged coagulation times. In anex vivocirculation model, the dual-peptide coating dramatically reduced thrombus formation. This integrated strategy, which combines precise control over peptide presentation with the synergistic functions of EPC recruitment, immune modulation, and multi-mechanism anticoagulation, presents a promising and versatile platform for engineering the next generation of advanced cardiovascular stents.