Surface-anchored framework for generating RhD-epitope stealth red blood cells

Rhesus D (RhD) is one of the most important immunogenic antigens on red blood cells (RBCs). However, the supply of RhD-negative blood frequently faces critical shortages in clinical practice, and the positive-to-negative transition of the RhD antigen remains a great challenge. Here, we developed an alternative approach for sheltering the epitopes on RhD-positive RBCs using a surface-anchored framework, which is flexible but can achieve an optimal shield effect with minimal physicochemical influence on the cell. The chemical framework completely obstructed the RhD antigens on the cell surface, and the assessments of both blood transfusion in a mouse model and immunostimulation with human RhD-positive RBCs in a rabbit model confirmed the RhD-epitope stealth characteristics of the engineered RBCs. This work provides an efficient methodology for improving the cell surface for universal blood transfusion and generally indicates the potential of rationally designed cell surface engineering for transfusion and transplantation medicine.