Milk EVs Promote Apical Periodontitis Bone Repair via Osteoblast Targeting

Chronic apical periodontitis (CAP), an inflammatory disease of periapical tissues, leads to alveolar bone destruction. Current therapies lack osteoblast-targeting specificity and fail to effectively promote bone repair. Extracellular vesicles (EVs), particularly milk-derived EVs (MEVs), show potential for bone regeneration and have anti-inflammatory effects. We investigated the therapeutic potential of engineered MEVs modified with the osteoblast-targeting peptide DSPE-PEG-Mal-Cys-SDSSD (DPS) in CAP. DPS-MEVs enhanced osteogenic capacity and exhibited greater osteoblast targeting compared with unmodified MEVs through oxidative phosphorylation (OXPHOS) activation, driven by Kruppel-like factor 4 (KLF4)–mediated upregulation of NADH dehydrogenase 1 alpha subcomplex 4 (Ndufa4) in vivo and in vitro. We also transplanted DPS-MEVs into a CAP model of dogs through apical microsurgery and found that DPS-MEVs enhanced bone repair and reduced inflammation by promoting polarization of M2 macrophages. These findings highlighted the potential of engineered DPS-MEVs as a dual-functional therapy for CAP, combining immunomodulation and tissue repair to advance precision treatment for inflammatory bone diseases.