Red Blood Cells Internalize Extracellular DNA via Apoptotic Bodies with Clinical Relevance to Cancer Patients

Mature red blood cells (RBCs), the most abundant anucleate cells in humans, have long been overlooked as DNA carriers. Recent evidence implicates RBC-derived DNA (rbcDNA) as a potential biomarker for cancer diagnostics, yet its origin 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-free 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-treated RBCs are rapidly cleared in vivo via a partly macrophage-dependent 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.