Metformin-loaded mesoporous calcium silicate nanoparticles against alkaline-resistant Enterococcus faecalis infection

Background Enterococcus faecalis (E. faecalis) contributes to persistent endodontic infections through biofilm formation, dentinal tubule invasion, and alkaline resistance, which limits the efficacy of calcium hydroxide. Metformin (Met) attenuates this resistance by interfering with bacterial metabolic adaptation. Combining Met with mesoporous calcium silicate nanoparticles (MCSNs), which possess intrinsic alkaline antibacterial activity and sustained drug-delivery capabilities, may enhance the elimination of alkaline-resistant E. faecalis and promote periapical healing.Methods Metformin-loaded MCSNs (MCSNs-Met) were characterized for physicochemical properties, Met release, alkalinity, cytocompatibility, and dentinal tubule penetration. Antibiofilm activity against highly alkaline-resistant E. faecalis was assessed using infected dentin models. Therapeutic efficacy was further evaluated in a beagle model of E. faecalis-induced apical periodontitis using Micro-CT and histological analyses.Results MCSNs-Met exhibited a uniform mesoporous structure, sustained Met release and alkalinity, favorable cytocompatibility, and enhanced dentinal tubule penetration. Compared with MCSNs alone, MCSNs-Met more effectively disrupted E. faecalis biofilms and reduced viable bacterial signals. In vivo, MCSNs-Met produced the greatest reduction in periapical bone resorption, markedly decreased residual bacterial signals and inflammatory infiltration, reduced osteoclast activity, and enhanced collagen deposition and periapical tissue repair.Conclusions MCSNs-Met integrates sustained Met delivery with the intrinsic alkaline and bioactive properties of calcium silicate nanoparticles, thereby enhancing control of highly alkaline-resistant E. faecalis and promoting periapical healing.