Methacrylated hyaluronic acid hydrogel enables CD44-mediated local berberine delivery to reprogram macrophage immunometabolism and promote alveolar bone repair in periodontitis.

Periodontitis is a chronic inflammatory disease characterized by persistent immune dysregulation and progressive alveolar bone loss. Here, reanalysis of single-cell transcriptomic data from human gingival tissues identified CD44+ macrophages as an expanded macrophage subset in periodontal lesions with proinflammatory and glycolytic features. To therapeutically modulate this population without relying on conventional antibiotics, we developed a local immunometabolic delivery platform (MHA-B@Lipo) by incorporating berberine-loaded liposomes into a methacrylated hyaluronic acid (MHA) hydrogel. Through localized hydrogel retention, inflammatory microenvironment-responsive network degradation, and HA-CD44-mediated cellular uptake, MHA-B@Lipo improved berberine delivery to CD44+ macrophages. Intracellularly, berberine reduced glycolytic activity and lactate accumulation, accompanied by suppression of the HIF-1α/GLUT1-related signaling and a metabolic shift toward mitochondrial oxidative phosphorylation. These changes promoted macrophage repolarization toward a reparative phenotype and established a pro-osteogenic microenvironment that supported the osteogenic responses of bone marrow stromal cells. In a rat ligature-induced periodontitis model, local administration of MHA-B@Lipo alleviated periodontal inflammation, preserved collagen tissue architecture, and promoted alveolar bone repair with efficacy comparable to minocycline. Together, these findings present a human tissue-informed, antibiotic-free strategy that couples localized biomaterial retention with immunometabolic rewiring for inflammatory bone repair.