Interfacial Coordination-Engineered Emulgel Modulates the Osteo-Immune Microenvironment in Periodontitis Treatment Via HIF1 Signaling Pathway-Induced Metabolic Reprogramming.

A multifunctional high internal phase Pickering emulsion (HIPPE-QU) is developed to address immune dysregulation in periodontitis by reprogramming macrophage metabolism and promoting tissue regeneration. Fabricated via one-step homogenization, HIPPE-QU features a 75% internal phase and is co-stabilized by gelatin nanoparticles (GNPs) and copper-doped hydroxyapatite (HA-Cu), forming a gel-like, injectable emulgel suitable for clinical application. Hydrophobic quercetin (QU) is encapsulated in the internal phase and chelates with Cu(2)⁺ and Ca(2)⁺ at the interface, enabling sustained and pH-responsive release under the acidic periodontal environment. The spatially organized loading strategy across dispersed, interfacial, and internal phases yields synergistic antibacterial and immunoregulatory effects. Mechanistically, HIPPE-QU modulates macrophage glycolysis and ATP metabolism via HIF-1 signaling, suppresses ROS overproduction, and promotes M1-to-M2 polarization. In vivo, HIPPE-QU alleviates inflammation, restores BMSC osteogenic capacity, and enhances periodontal tissue regeneration. This work presents an innovative immune-reprogramming platform with translational potential for precision modulation of the periodontal immune microenvironment.