A dual-gas release system combined with a zwitterionic coating promotes ideal vascular regeneration in small-diameter vascular grafts

• A hydrogen sulfide-releasing keratin-based donor with excellent hydrophilicity and biocompatibility was prepared. • A zwitterionic composite coating was developed to simulate endothelialization. • A dual-gas (nitric oxide/hydrogen sulfide) synergistic system was constructed to promote the vascularization of small-diameter vascular graft. This study developed a small-diameter vascular graft featuring a dual-gas (NO and H 2 S) release system combined with a zwitterionic coating, aiming to address three major challenges: thrombosis, delayed endothelialization, and intimal hyperplasia. By blending a keratin-conjugated H 2 S donor (KBT) with poly(L-lactide-co-ε-caprolactone) (PLCL) for electrospinning, and further modifying the graft with a dopamine–copper–amine‑terminated sulfobetaine (SB) composite coating, a PLCL/KBT-SB vascular graft capable of sustained catalytic release of NO and H 2 S was fabricated. In vitro experiments confirmed the ability to selectively promote endothelial cell proliferation and migration while inhibiting smooth muscle cell activity. The zwitterionic coating and the synergistic dual-gas release system effectively reduced protein adsorption and polarized macrophages toward M2 phenotype. The PLCL/KBT-SB graft was further evaluated in vivo using a rat abdominal aorta replacement model (n = 8 per group). Histological assessment revealed that the graft reduced the inflammatory state of endothelial cells, promoted endothelial functional maturation, and facilitated the transition of smooth muscle cells toward a contractile phenotype. Furthermore, the grafts demonstrated uniform neotissue distribution at both 1 and 3 months post-implantation, with moderate neointimal thickness and no calcification. Overall, this study provides a promising small-diameter vascular grafts by innovatively integrating gas therapy and surface modification strategies.