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Recent evidence\u00a0implicates RBC\u2010derived DNA (rbcDNA) as a potential biomarker for cancer diagnostics, yet its\u00a0origin and how RBCs acquire tumor DNA remain poorly understood. Here, we find that mature RBCs harbor short DNA fragments distinct from genomic DNA. Both in vivo and in vitro experiments confirm that RBCs can internalize extracellular DNA and reflect tumor burden. Oxford Nanopore sequencing of rbcDNA reveals that short rbcDNA fragments are homologous to extracellular cell\u2010free DNA (cfDNA). We identify apoptotic bodies (apoBDs) as key mediators of extracellular DNA uptake by RBCs, triggering RBC deformation, Heinz body formation, oxidative stress, and vesiculation. Tumor apoBD\u2010treated RBCs are rapidly cleared in vivo via a partly macrophage\u2010dependent effect, causing local immunosuppression in the spleen. Clinically, rbcDNA shows no advantage in detecting driver mutations compared with cfDNA, but its abundance significantly correlates with tumor burden and treatment response. Overall, our findings offer novel insights into RBC biology and support rbcDNA's clinical application in liquid biopsy.<\/jats:p>","DOI":"10.1002\/advs.202511408","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T07:51:37Z","timestamp":1767599497000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Red Blood Cells Internalize Extracellular DNA via Apoptotic Bodies with Clinical Relevance to Cancer Patients"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1900-8478","authenticated-orcid":false,"given":"Zihang","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors Hubei Provincial Clinical Research Center For Cancer Zhongnan Hospital of Wuhan University Wuhan University  Wuhan 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Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixiang","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors Hubei Provincial Clinical Research Center For Cancer Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors Hubei Provincial Clinical Research Center For Cancer Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirui","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors 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Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors Hubei Provincial Clinical Research Center For Cancer Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological Behaviors Hubei Provincial Clinical Research Center For Cancer Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"},{"name":"Taikang Center for Life and Medical Sciences Wuhan University  Wuhan 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