Fighting periodontitis with a pH-triggered nanocoating: A sustained-release strategy for simvastatin delivery.

The growing incidence of periodontitis demands innovative therapies, as current drug treatments are limited by short retention times, rapid clearance, and the risk of antimicrobial resistance. This study introduces a novel pH-responsive nano-miclle system for simvastatin (SIM) delivery. Its core innovation lies in being the first system ((SIM NP)n) of its kind to be stabilized by a cross-linked "outer shell," which significantly enhances its stability and controlled release capabilities. This "smart" system remains stable in a neutral environment (pH 7.4), preventing premature drug release. However, upon encountering the acidic inflammatory microenvironment of periodontitis, the shell degrades, triggering the sustained release of SIM directly at the site of inflammation. In vitro studies demonstrated that the SIM-loaded micelles possess potent immunomodulatory effects: they effectively suppressed pro-inflammatory M1 macrophage polarization (decreasing IL-1β, iNOS) while promoting anti-inflammatory M2 macrophage polarization (increasing Arg-1, IL-10). Mechanistic investigation confirmed this therapeutic effect is mediated by the PI3K/AKT/mTOR signaling pathway. More importantly, in a mouse model of periodontitis, the nano-micelles significantly reduced alveolar bone resorption, demonstrating potent anti-inflammatory and bone-protective efficacy in vivo. In conclusion, this "smart" pH-triggered delivery system for SIM offers a highly promising and effective strategy to overcome the limitations of traditional therapies, providing a new targeted path for the treatment of periodontitis.