In the context of inflammation, autoimmune diseases, infections, and cancers, cfDNA plays a pivotal role in disease progression through various mechanisms. Immunotherapies based on cfDNA scavenging has emerged as a promising approach for treating these conditions. This review offers a comprehensive exploration of cfDNA-binding and degradation strategies, providing detailed insights into the corresponding nano/microsystems for each approach. Nano/microsystems used for cfDNA binding include cationic polymers, nanoparticles, nanogels, and other materials that physically capture cfDNA via electrostatic interactions or other affinity mechanisms, thereby mitigating the immunological effects of cfDNA. Nano/microsystems designed for cfDNA degradation primarily involve DNase delivery systems and artificial enzymes with DNase-like activity, which degrade cfDNA through chemical cleavage. Furthermore, this review discusses the potential synergy between cfDNA-scavenging therapies and other treatment modalities, aiming to achieve more effective and comprehensive immunotherapy. By thoroughly analyzing these strategies, we aim to emphasize the transformative potential of cfDNA-scavenging nano/microsystems in advancing immunotherapy, and offer valuable perspectives for future research in this emerging field.