Engineering the Universal Donor: CRISPR-Mediated Blood Group Antigen Deletion and the Path Toward Truly Universal Red Blood Cells—A Narrative Review

The designation of O RhD-negative blood as a “universal donor” misrepresents the complexity of red blood cell (RBC) compatibility. With 47 recognized blood group systems encompassing 366 antigens, non-ABO antigen exposure drives alloimmunization in 20–50% of chronically transfused patients. A narrative review of PubMed, Scopus, and EMBASE was conducted for studies published between 2016 and 2025, with selective inclusion of foundational pre-2016 works. Enzymatic approaches using Flavonifractor plautii CAZymes and Akkermansia muciniphila exoglycosidase cocktails enable near-complete ABO antigen removal, though group A conversion remains incomplete. CRISPR-Cas9 multiplex editing of immortalized erythroblasts has achieved simultaneous deletion of ABO, Rh, Kell, Duffy, and MNS antigens. Induced pluripotent stem cell platforms enable scalable manufacture; however, enucleation efficiency (40–70%), yield (4.6 × 103 RBCs/iPSC), and fetal hemoglobin prevalence remain translational barriers. Convergence of enzymatic and gene-editing technologies on GMP-compatible iPSC platforms represents the most credible pathway to truly universal RBCs, although current evidence remains largely confined to immortalized cell lines and early-stage iPSC proof-of-concept studies rather than clinically validated products. Regulatory frameworks, scalability, and rigorous off-target profiling define the key challenges ahead.