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Cell\u2010free DNA (cfDNA) is not only a biomarker for various inflammatory diseases, but also a driver in innate immune responses, offering emerging diagnostic and therapeutic possibilities for inflammatory diseases. This review begins by examining immune signatures in inflammation, with particular focus on the vicious cycle between cfDNA and inflammatory responses. We then discuss cfDNA detection strategies and their clinical applications as disease biomarkers. Crucially, we highlight design principles and formulation strategies for cfDNA\u2010based interventions for inflammation regulation, considering physical, biochemical, and immunological properties of cfDNA. These approaches encompass advanced nanotechnologies such as drug loading, targeted delivery, inflammation\u2010responsive release, and microenvironment reprogramming. 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