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

Abstract 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.