In this study, we investigated the relationship between cfDNA levels and severity of periodontal inflammation, characterized the DNA binding affinity and TLR9-inhibitory activity of G3@SeHANs, elucidated the cfDNA-scavenging mechanisms of G3@SeHANs and PAMAM-G3 and their activities in modulating the M1/M2 macrophage phenotypes, and finally compared the efficacy of these two scavenging configurations in reducing inflammatory bone loss in a ligature-induced periodontitis murine model. Here, TLR9 is linked to periodontitis.