Host Cell Membrane‐Cloaked Nanomedicine Reprograms Endothelial Surface for Enhanced Patency in Allogeneic Vascular Grafts

Abstract The endothelium serves as the first point of contact following the implantation of allogeneic vascular grafts (AGs) or organs. Rapid endothelial injury triggered by immunocytotoxicity, combined with subsequent endothelial dysfunction during vascular tissue remodeling, collectively exacerbates complications, including thrombosis, inflammation, and intimal hyperplasia, ultimately leading to graft failure. In this study, a nanomedicine, R‐SB@PLGA, is developed for use in metabolically guided cell surface reprogramming (CSR) in AGs. R‐SB@PLGA is fabricated by encapsulating SB431542 (SB)‐loaded poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles within host red blood cell membranes (RBCM). Upon immobilization, this nanomedicine reprograms the epitope presentation of endothelial cells (ECs), establishing localized steric immune shielding to preserve endothelial integrity without the need for systemic immunosuppression. Concurrently, the nanomedicine releases SB to inhibit the transforming growth factor‐β (TGF‐ β )‐mediated endothelial‐to‐mesenchymal transition (EndMT), thereby preventing endothelial dysfunction during vascular tissue remodeling. In animal models of allogeneic carotid artery transplantation, R‐SB@PLGA showed significant efficacy in enhancing graft patency by reducing vascular inflammation and intimal hyperplasia. By integrating site‐specific immune shielding with in situ therapeutic delivery, a novel paradigm is established for improving transplant outcomes through localized intervention, which is highly promising for promoting the success of allogeneic vascular or organ transplantation.