{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:44:40Z","timestamp":1785757480423,"version":"3.56.0"},"reference-count":71,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>The designation of O RhD-negative blood as a \u201cuniversal donor\u201d 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\u201350% 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\u201370%), yield (4.6 \u00d7 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.<\/jats:p>","DOI":"10.3390\/diagnostics16152448","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:24:07Z","timestamp":1785752647000},"page":"2448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering the Universal Donor: CRISPR-Mediated Blood Group Antigen Deletion and the Path Toward Truly Universal Red Blood Cells\u2014A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3394-0686","authenticated-orcid":false,"given":"Malik A.","family":"Altayar","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). 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