Stealth red blood cells with broad-spectrum antigenic shielding for transfusion therapy in antibody-mediated hemolytic anemia.

Red blood cell (RBC) transfusion is a cornerstone of life-sustaining therapy, yet it is profoundly challenged in autoimmune hemolytic anemia (AIHA). In this disorder, a diverse array of autoantibodies targets both the autologous and transfused RBCs, leading to their rapid clearance. This limitation is especially severe during hemolytic crises, rendering conventional transfusion ineffective and eliminating a critical therapeutic option. To overcome this, we developed a biocompatible strategy by utilizing a microbial transglutaminase that first anchors to the RBC membrane and then crosslinks a polysialic acid (PSA) network onto the cell surface. This created an immunologically inert shield that broadly masks surface antigens from pathogenic antibodies. Crucially, this "stealth" modification preserved the RBCs' native biological functions, including essential gas exchange, while conferring robust resistance to antibody-mediated hemolysis. In vitro, the engineered RBCs were protected from antibody binding and macrophage phagocytosis. This protection translated to a significantly prolonged circulation time in AIHA murine models and demonstrated excellent biocompatibility in an allogeneic transfusion setting. Our findings underscore the significant potential of this platform to enable effective, life-saving transfusion therapies for AIHA and other antibody-mediated disorders.