Targeting iron overload and macrophage polarization to treat diabetic periodontitis: Mechanisms and therapeutic strategies.

Diabetic periodontitis (T2DM-CP, type 2 diabetes mellitus-associated chronic periodontitis) is exacerbated by iron overload and macrophage imbalance, but therapeutic strategies remain limited. We analyzed macrophage polarization and iron metabolism markers in T2DM-CP patients and high glucose-treated macrophages, then evaluated deferoxamine (DFO) and chitosan hydrogel containing black phosphorus (BP) nanosheets and Dl-3-n-butylphthalide (NBP) (CH-BPNs-NBP) as targeted therapies. Clinical T2DM-CP samples and high glucose-stimulated macrophages showed increased M1 markers (iNOS) with decreased M2 markers (ARG-1), along with iron dysregulation (elevated TfR1, reduced FPN1 and GPX4). High glucose conditions induced ferroptosis, evidenced by mitochondrial damage and lipid peroxidation. While DFO treatment partially restored macrophage balance and iron homeostasis, CH-BPNs-NBP demonstrated more comprehensive therapeutic effects by effectively scavenging reactive oxygen species, promoting macrophage polarization toward the M2 phenotype, normalizing iron metabolism markers, and reducing alveolar bone loss as measured by CEJ-ABC distance. These findings establish iron overload and macrophage polarization as key pathological mechanisms in T2DM-CP and identify CH-BPNs-NBP as a promising multifunctional therapy capable of simultaneously addressing oxidative stress, iron dysregulation, and inflammatory imbalance in diabetic periodontitis. The superior efficacy of CH-BPNs-NBP suggests strong potential for clinical translation in managing this diabetic complication.