Cell-free DNA in precision medicine: overcoming biological barriers through integrated nanoparticle platforms for simultaneous diagnosis and therapy

Cell-free DNA (cfDNA), released into the bloodstream through cell death and cellular stress, has emerged as a highly promising noninvasive biomarker with broad diagnostic and therapeutic potential. However, clinical translation of cfDNA remains limited by its intrinsic properties, including extensive fragmentation, very low circulating concentrations, and extreme susceptibility to degradation by blood nucleases. Recent advances in nanoparticle-based nanotechnology have provided powerful solutions to overcome these barriers. In diagnostics, functionalized nanoparticles enable ultrasensitive and highly specific detection of cfDNA directly in blood, thereby facilitating early cancer detection, noninvasive prenatal screening, and real-time monitoring of diverse pathologies. Beyond diagnostics, cationic and multifunctional nanoparticles can actively bind and remove extracellular cfDNA from circulation, neutralizing its pro-inflammatory role as a damage-associated molecular pattern in conditions such as sepsis, rheumatoid arthritis, and cancers. Despite these advances, no comprehensive review has yet integrated cfDNA-based diagnostic and therapeutic strategies within a unified nanotechnological framework. Existing studies remain largely siloed, focusing independently on oncological biosensors, prenatal testing, or inflammatory processes in specific diseases. This fragmentation has hindered synergistic translational progress and efficient clinical implementation. This review systematically examines recent interdisciplinary advances at the intersection of nanotechnology and cfDNA research. By highlighting current challenges and opportunities, it outlines future directions toward realizing precision medicine applications that simultaneously exploit the diagnostic and therapeutic potential of cfDNA through integrated nanoparticle platforms.