Biomaterial-based strategies for cell-free nucleic acids scavenging and macrophage modulation in oral diseases: Mechanisms and therapeutic potential.

Abstract

Cell-free nucleic acids (cfNAs), including cfDNA and cfRNA, have emerged as potent drivers of inflammation and immune dysregulation in oral diseases by activating nucleic acid-sensing pathways and inducing macrophage polarization. These processes disrupt immune homeostasis and impair tissue regeneration, positioning cfNAs not only as biomarkers but also as active immunological effectors. Recent advances highlight the therapeutic potential of biomaterial-based strategies for scavenging cfNAs and modulating macrophage phenotypes. These include cationic polymers, nanoparticles, hydrogels, micro/nanogels, nano/microfibers, microneedles, and enzymatic or artificial nuclease systems. This review systematically outlines cfNA-sensing mechanisms and the resulting macrophage-mediated immune responses that drive oral pathologies, and discusses emerging biomaterial platforms designed to restore immune balance and facilitate tissue repair. These insights underscore the translational promise of cfNA-scavenging immunotherapies across a broad spectrum of oral diseases.