From biomarkers to therapeutic targets: Biomaterial-mediated cfDNA scavenging in inflammation.

Abstract

Cell-free DNA (cfDNA) displays disease-dependent changes in abundance, fragmentation, composition, and tissue origin. Beyond serving as a noninvasive biomarker, persistent cfDNA can act as a damage-associated molecular pattern, activating TLR9, cGAS-STING, inflammasome signaling, and thromboinflammation. This review synthesizes advances in cfDNA biology, clinical applications, and therapeutic scavenging across inflammatory diseases. We critically evaluate the extent to which current clinical studies support diagnostic, prognostic, and causal conclusions while considering methodological heterogeneity. Particular emphasis is placed on how biomaterials transform cfDNA recognition into treatment. We trace the evolution from free nucleases and soluble cationic agents to nanostructured platforms that integrate DNA sequestration with retention, degradation, lesion targeting, or immunomodulation. Comparison of cationic polymers, dendrimers, core-shell nanoparticles, hydrogels, microneedles, nanosheets, and nuclease-enabled systems reveals how material architecture governs cfDNA accessibility, stability in biofluids, tissue distribution, and therapeutic efficacy. Localized and stimuli-responsive designs may improve selectivity and reduce systemic toxicity, but most efficacy evidence remains preclinical. Clinical translation therefore requires standardized cfDNA measurement, realistic biofluid testing, rigorous pharmacology, scalable manufacturing, and prospective demonstration that selective cfDNA removal improves outcomes without compromising host defense.