Emerging roles of platelet DNA in cancer detection and noninvasive prenatal testing

Cell-free DNA (cfDNA) level is a core liquid biopsy biomarker. However, it exhibits low detection sensitivity in early-stage diseases and carries a risk of information loss. Traditionally regarded as anucleate and DNA-deficient, platelets have recently been confirmed to actively take up and carry extracellular DNA-termed platelet DNA (pDNA). We summarized pDNA uptake mechanisms, including clathrin-mediated endocytosis of DNA-loaded extracellular vesicles and direct internalization of free DNA, as well as its pharmacological regulation. Compared with plasma cfDNA levels, pDNA shows superior stability, higher mutant allele frequencies, and resistance to nucleases. We elaborated its clinical potential for early cancer detection by capturing low-abundance tumor mutations and for noninvasive prenatal testing by overcoming the scarcity of fetal cfDNA in early pregnancy. Finally, we discussed integrating pDNA analysis using multiomics and artificial intelligence to advance precision liquid biopsy. SIGNIFICANCE STATEMENT: Platelet DNA level reshapes platelets' role from hemostatic cells to genetic carriers, resolving plasma cell-free DNA level's limitations. It enables early cancer detection and prenatal testing, advancing liquid biopsy toward precision medicine for better diagnostic outcomes.