PLGA nanoparticles co-loaded with resveratrol and doxycycline for dual-action periodontal therapy: in vitro and in vivo evaluation

Periodontitis is a chronic inflammatory disease caused by a dysbiotic subgingival biofilm that triggers an imbalanced host immune response. This study developed and evaluated poly(lactic-co-glycolic acid) (PLGA) nanoparticles co-loaded with doxycycline (DOX) and resveratrol (RV) for dual-action periodontal therapy. Nanoparticles were prepared by double-emulsion solvent evaporation and characterized for size, charge, encapsulation efficiency, release kinetics, antimicrobial activity, cytocompatibility, and osteogenic effects in vitro and in vivo. The co-loaded nanoparticles (PLGA-DOX/RV) had a mean size of 256.6 ± 13.4 nm, zeta potential of −17.3 ± 2.2 mV, and encapsulation efficiencies of 94.6% (DOX) and 95.8% (RV). In vitro release showed a biphasic profile, with cumulative release reaching 67.6% and 75.9% at 72 h, respectively. PLGA-DOX/RV reduced minimum inhibitory and bactericidal concentrations fourfold against P. gingivalis and A. actinomycetemcomitans, and inhibited biofilm formation by >55%. Cytotoxicity assays indicated 65.3% fibroblast viability at 200 µg/mL, while alkaline phosphatase activity increased by 67.3%. In vivo, PLGA-DOX/RV reduced alveolar bone loss (0.65 mm vs. 0.89 mm in control) and lowered IL-1β, IL-6, and TNF-α by 67.4%, 80.1%, and 74.2%, respectively. These results demonstrate PLGA-DOX/RV as a potent localized therapy for periodontitis.