Phosphatidylserine‐Externalized Erythrocyte Membrane Biointerface Redefines Endogenous Immunomodulation for Small‐Diameter Vascular Grafts

Autologous erythrocyte membranes are widely recognized for their immune evasion properties and have been extensively explored as drug delivery carriers. However, their potential to actively instruct host immunity through immune‐engulfment pathways remains largely unexplored. Here we redefine the immunological function of erythrocyte membranes by engineering phosphatidylserine (PS) externalization, transforming an immune escape into an immune‐engulfment phenotype. PS‐externalized erythrocyte membrane vesicles (PS‐EMVs) are precisely conjugated with the endogenous antimicrobial peptide LL37, and through bioorthogonal azide (N 3 )‐dibenzocyclooctyne (DBCO) click chemistry, establish an immunomodulatory and anti‐infective interface for small‐diameter vascular grafts (SDVGs). PS exposure serves as the primary immunomodulatory cue by activating efferocytosis‐associated pathways, suppressing inflammatory responses, and promoting vascular regeneration. LL37 provides antimicrobial protection while preserving the PS‐mediated immune‐resolving program and is associated with reduced vascular smooth muscle contractility and metabolic stress. In vivo, SDVGs functionalized with PS‐EMVs‐LL37 interfaces exhibit enhanced hemocompatibility, accelerated endothelialization, and reduced calcification. This autologous, scalable strategy provides a translational framework for personalized vascular grafts and broader immuno‐guided design of blood‐contacting devices.