Poly(L-lactic-co-caprolactone)-nano hydroxyapatite promotes periodontal bone regeneration via mitochondrial metabolism-driven macrophage reprogramming

Abstract Periodontitis, a chronic inflammatory disease causing progressive bone loss, demands biomaterials that simultaneously resolve inflammation and promote regeneration. Poly(L-lactic-co-caprolactone)-nano hydroxyapatite (PLCL-nHA) combines mechanical durability with bioactive potential, yet its precise immunomodulatory actions within inflammatory microenvironments remain unclear. This study demonstrates that PLCL-nHA restores periodontal homeostasis by suppressing inflammatory cascades and steering macrophage functional reprogramming. In a murine periodontitis model, PLCL-nHA implantation reduced alveolar bone resorption, altered the gingival microbiota profile (including reduction of Lactobacillus/Enterococcus), and suppressed osteoclastic activity. In vitro, PLCL-nHA suppressed LPS-induced pro-inflammatory cytokines and oxidative stress while promoting M2 macrophage polarization. Mechanistically, PLCL-nHA enhanced mitochondrial energy metabolism, which inhibited nuclear factor kappa B (NF-κB) activation. Rat bone defects confirmed accelerated inflammatory resolution and osteogenesis. These findings establish PLCL-nHA as a dual-functional scaffold that coordinates immunometabolic adaptation and tissue repair, providing a paradigm for metabolism-oriented resolution of inflammation in periodontitis and related osteolytic disorders.