A piezoelectric hydrogel was developed to treat periodontitis by activating bioenergetic processes and modulating the immune microenvironment. The hydrogel, composed of tetragonal barium titanate (t-BTO) nanoparticles and tilapia gelatin, generates piezopotential under mechanical stress, which enhances the osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) by modulating energy metabolism and ATP synthesis. It also switches macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, promoting tissue regeneration. In vitro studies showed that t-BTO US+ treatment significantly increased ATP levels, mitochondrial membrane potential, and osteogenic gene expression in PDLSCs. RNA sequencing revealed upregulation of genes related to energy metabolism, cytoskeleton organization, and phosphatidylinositol signaling. In vivo experiments in rats demonstrated that the hydrogel effectively regenerated bone tissue in periodontal defects, with the GelMA + t-BTO group showing the highest bone volume and mineral density after 12 weeks. The hydrogel's piezoelectric properties enabled wireless, self-powered stimulation, making it a promising treatment for periodontitis and other immune-related bone defects.A piezoelectric hydrogel was developed to treat periodontitis by activating bioenergetic processes and modulating the immune microenvironment. The hydrogel, composed of tetragonal barium titanate (t-BTO) nanoparticles and tilapia gelatin, generates piezopotential under mechanical stress, which enhances the osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) by modulating energy metabolism and ATP synthesis. It also switches macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, promoting tissue regeneration. In vitro studies showed that t-BTO US+ treatment significantly increased ATP levels, mitochondrial membrane potential, and osteogenic gene expression in PDLSCs. RNA sequencing revealed upregulation of genes related to energy metabolism, cytoskeleton organization, and phosphatidylinositol signaling. In vivo experiments in rats demonstrated that the hydrogel effectively regenerated bone tissue in periodontal defects, with the GelMA + t-BTO group showing the highest bone volume and mineral density after 12 weeks. The hydrogel's piezoelectric properties enabled wireless, self-powered stimulation, making it a promising treatment for periodontitis and other immune-related bone defects.