Nature‐Inspired Histidine and Guanidine Modification of Magnetic Nanoparticles for Urinary DNA Liquid Biopsy

ABSTRACT Urinary cell‐free DNA (cfDNA) is a promising substrate for non‐invasive liquid biopsy analysis and biomarker detection. However, the lack of standardized pre‐analytical workflows and the intrinsic challenges associated with isolating highly dilute and fragmented cfDNA limit its broader research and clinical applications. Here, we present a simplified, reliable and cost‐effective extraction platform based on iron oxide nanoparticles (IONPs) synthesized via coprecipitation. By leveraging nature‐inspired surface functionalization, these magnetic nanoparticles enable the rapid and direct isolation of cfDNA from fresh urine while supporting scale‐up of the processing volumes. The proposed platform achieves a 2‐fold increase in cfDNA yield compared to conventional commercial extraction kits and demonstrates enhanced recovery of short DNA fragments, with a predominant size distribution between 80–150 bp. This improved capture efficiency facilitates a detection sensitivity down to 10 −3 ng/mL using qPCR, likely limited by assay sensitivity rather than DNA extraction performance. Moreover, the simplified extraction and elution steps eliminate the need for specialized laboratory instrumentation. Collectively, this approach provides a foundation for accessible, potentially at‐home cfDNA extraction and advances the development of truly non‐invasive diagnostic strategies for longitudinal disease monitoring and management.