Thermosensitive antibacterial nanocomposite hydrogel guiding macrophage polarization and bone regeneration for periodontitis treatment

Periodontitis is a chronic inflammatory disease caused by bacterial infection that leads to the destruction of periodontal tissues. Traditional treatment involves scaling and root planing combined with antibiotics, but systemic antibiotic therapy often results in insufficient drug concentration at the treatment site and unwanted side effects. Here, we developed a nanocomposite thermosensitive hydrogel (CFMD) designed for localized drug delivery. The chitosan-grafted Pluronic® F127 hydrogel (CP) had natural antibacterial activity. After the thermosensitive material flows into the periodontal pocket, it transforms into a gel phase at body temperature, filling the periodontal pocket and preserving the nanomedicine. As the hydrogel retained in the periodontal pocket is degraded, folic acid-modified MBG nanoparticles loaded with doxycycline (FA-MBG@Dox) nanoparticles deliver doxycycline hydrochloride (Dox) to below the gum line, where instruments and hydrogel drug carriers cannot reach, enabling deeper antibacterial, anti-inflammatory, and osteogenesis-promoting effects. In vitro , CFMD hydrogel exhibited potent antibacterial activity, promoted human periodontal ligament stem cells (hPDLSCs) differentiation, and induced macrophage polarization toward the anti-inflammatory (M2) phenotype. In vivo , it effectively inhibited alveolar bone loss, promoted bone regeneration, and reshaped the inflammatory microenvironment. This study showed that CFMD hydrogel with targeted polarization regulation, oxidative stress regulation and osteogenesis regeneration capabilities may provide a simpler and more effective way for the treatment of periodontitis. • Developed a targeting, long-term retention and deep penetration CFMD hydrogel for the treatment of periodontitis. • The hydrogel shows strong antibacterial and anti-inflammatory effects in vivo, promoting bone and periodontal regeneration. • CFMD hydrogel enables targeted drug delivery below the gum line, significantly reducing alveolar bone loss. • Effective inflammation control through M2 polarization reshapes the periodontal microenvironment.