A biomimetic nanoparticle coordinates antibacterial and immunomodulatory functions to promote periodontal regeneration

Periodontitis is a chronic inflammatory disorder driven by pathogenic microbial communities and an imbalanced host immune response, finally leading to progressive breakdown of periodontal soft and hard tissues. Current treatments primarily target infection but often fail to resolve inflammation or support subsequent tissue repair. Hence, we developed NMm@MINO, a biomimetic nanoparticle constructed by coating minocycline-loaded gelatin nanoparticles with a hybrid neutrophil-macrophage membrane. NMm@MINO formed a stable core-shell structure with a hydrodynamic diameter of (261.53 ± 11.59) nm and a membrane shell thickness of ~21 nm, maintaining colloidal stability for 30 days. Minocycline release was protease-responsive, with ~50% payload released within 2 h under gelatinase exposure and reaching equilibrium at ~8 h. In vitro, NMm@MINO achieved > 99% killing efficiency against Porphyromonas gingivalis and Staphylococcus aureus. Simultaneously, NMm@MINO reprogrammed polarization by downregulating M1-associated transcripts (Nos2, Tnf, Il1b, and Cd86) and upregulating M2-associated markers (Mrc1, Arg1, and Tgfb1), corroborated by decreased iNOS and increased CD206 immunofluorescence. NMm@MINO further enhanced osteogenesis (upregulating Alpl, Spp1, Runx2), suppressed RANKL-induced osteoclastogenesis (reduced TRAP staining and downregulated Acp5, Tnfrsf11a, Ctsk, Fos, and Mmp9; decreased c-Fos immunofluorescence), and promoted fibroblast migration with increased Collagen I immunofluorescence. In a ligature-induced rat periodontitis model (days 3, 7, and 14), local NMm@MINO reduced inflammation (IL-6/CRP IHC; decreased Il6, Crp, and Il1b), improved collagen remodeling (H&E/Masson; increased Col1a1), and mitigated alveolar bone loss (micro-CT: CEJ-ABC, BV/TV, Tb.N, Tb.Th, and Tb.Sp) while modulating osteoclast/osteogenic markers (TRAP, RANKL/OPG IHC; Acp5, Tnfsf11, Tnfrsf11b, and Runx2). Collectively, NMm@MINO coordinates antibacterial, immunomodulatory, and pro-regenerative actions for periodontitis therapy.