Targeted and Biosafe Delivery of Spermidine to Ameliorate Foreign Body Responses After Synthetic Vascular Graft Implantation In Vivo

Vascular grafts are crucial for treating cardiovascular diseases, but their clinical application is limited by poor regeneration due to foreign body reactions. Spermidine (SPD), a natural polyamine with anti‐inflammatory and antioxidant properties, shows promise in inhibiting inflammation in vitro but is challenged by the lack of targeting ability and high cytotoxicity in vivo. To address these issues, we developed platelet membrane fragments (PMFs)‐modified lipid nanoparticles (PLNPs) for targeted delivery of SPD (PLNP‐SPD) by adventitial administration to inflamed tissues around poly(ε‐caprolactone) (PCL) vascular grafts. PLNP‐SPD showed a spherical structure with integrated PMFs. In vitro, PLNP‐SPD selectively bound to inflamed macrophages via P‐selectin/PSGL‐1 interactions, promoted SPD internalization by macrophages through membrane fusion, and suppressed macrophage M1 polarization. In vivo, adventitial delivery of PLNP‐SPD surrounding PCL vascular grafts demonstrated selective accumulation in macrophages, reduced inflammation, and thus improved vascular regeneration. PLNP‐SPD also exhibited excellent biosafety with minimal systemic toxicity. This study highlights PLNP‐SPD as a novel nanoplatform for targeted SPD delivery in vivo, which offers a promising strategy to mitigate foreign body reactions caused by graft implantation and promote vascular regeneration.