This study explores the potential of lithiated porous silicon nanowires (LipSiNs) for periodontal regeneration. Periodontal disease, a significant oral health issue, causes irreversible damage to the periodontium, including bone, cementum, and periodontal ligament. LipSiNs are prepared using metal-assisted chemical etching (MACE) to create porous silicon nanowires, which are then lithiated with lithium precursors to incorporate up to 40% lithium by weight. The lithiation process is optimized to control the amount and kinetics of ion release, with lithium and silicic acid released in a tunable manner over days to weeks. LipSiNs combine osteogenic, cementogenic, and Wnt/β-catenin stimuli to promote bone, cementum, and periodontal ligament regeneration in a murine model of periodontal defects. In vitro, LipSiNs improve the biocompatibility and osteogenic activity of human periodontal ligament stem cells (hPDLCs). In vivo, LipSiNs significantly enhance bone mineral density and volume, and stimulate the regeneration of cementum and periodontal ligament fibers compared to other treatments, including lithium chloride, porous silicon nanowires, and a commercial guided tissue regeneration membrane. The study demonstrates the potential of LipSiNs as a promising material for periodontal regeneration, with controlled ion release and effective regenerative stimuli.This study explores the potential of lithiated porous silicon nanowires (LipSiNs) for periodontal regeneration. Periodontal disease, a significant oral health issue, causes irreversible damage to the periodontium, including bone, cementum, and periodontal ligament. LipSiNs are prepared using metal-assisted chemical etching (MACE) to create porous silicon nanowires, which are then lithiated with lithium precursors to incorporate up to 40% lithium by weight. The lithiation process is optimized to control the amount and kinetics of ion release, with lithium and silicic acid released in a tunable manner over days to weeks. LipSiNs combine osteogenic, cementogenic, and Wnt/β-catenin stimuli to promote bone, cementum, and periodontal ligament regeneration in a murine model of periodontal defects. In vitro, LipSiNs improve the biocompatibility and osteogenic activity of human periodontal ligament stem cells (hPDLCs). In vivo, LipSiNs significantly enhance bone mineral density and volume, and stimulate the regeneration of cementum and periodontal ligament fibers compared to other treatments, including lithium chloride, porous silicon nanowires, and a commercial guided tissue regeneration membrane. The study demonstrates the potential of LipSiNs as a promising material for periodontal regeneration, with controlled ion release and effective regenerative stimuli.