The objective of this study was to develop a type of universal blood cell based on a cell surface–anchored 3D framework for blood transfusion in emergency situations without the need for blood type matching. Cell surface engineering of RBCs was conducted by the self-assembly of lipid-like anchor molecules, and a uniform nanogel layer composed of PSA and tyramine was generated on individual RBCs through catalysis by surface-anchored enzymes. We first characterized the results of the cellular shell on the RBCs by fluorescence identification and electron microscopy and then demonstrated that the surface-anchored framework could prevent antibody-mediated aggregation in vitro using microplate-based assays, with further identification by flow cytometry. Next, we tested the physiochemical and biofunctional properties of the engineered RBCs to confirm that the cell surface framework did not affect the key functions of the RBCs. Last, we performed blood transfusion in a mouse model and immunostimulation with human RhD-positive RBCs in a rabbit model to confirm the biocompatibility, biofunctionality, and universal stealth characteristics of the engineered RhD-negative RBCs.

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