Melanin‐derived Biomimetic Nanoparticles Improve Patency and Tissue Regeneration of Vascular Grafts via ROS Scavenging and Immunomodulation in an Atherosclerotic Rat Model

Abstract Surgically bypassing or replacing using biodegradable synthetic small diameter vascular grafts (SDVGs) have garnered significant attention. However, complications such as thrombosis and foreign polymer‐induced local inflammation severely impair graft patency in vivo. To address these challenges, a biomimetic nanoparticle is developed, composed of melanin (MN) camouflaged with red blood cell membrane (denoted “MN@RM”), and co‐immobilized with heparin to functionalize the surface of electrospun PCL grafts (denoted as “PCL‐Hep/MN@RM”). MN@RM protect human umbilical vein endothelial cells and restrict the endothelial‐to‐mesenchymal transition through scavenging reactive oxygen species (ROS). In vitro studies demonstrate that MN@RM also promote macrophage polarization from a pro‐inflammatory phenotype toward an anti‐inflammatory phenotype. Additionally, RM, together with heparin shows excellent hemocompatibility. The graft exhibited enhanced endothelialization, improved local inflammation resolution and smooth muscle tissue regeneration in vivo. Single‐cell transcriptomic analysis further elucidated the major cell types involved in vascular graft remodeling and confirmed the regulatory role of macrophages. To simulate atherosclerotic environments, an ApoE −/− rat replacement model is established, where PCL‐Hep/MN@RM grafts demonstrated superior vascular patency and tissue regeneration. This study synergizes the advantages of synthetic polymers and biomimetic nanoparticles, offering a promising strategy for designing SDVGs and ROS‐scavenging biomaterials with potential applications in tissue regeneration beyond vascular repair.