The impaired differentiation ability of resident cells and disordered immune microenvironment in periodontitis pose a huge challenge for bone regeneration. Herein, we construct a piezoelectric hydrogel to rescue the impaired osteogenic capability and rebuild the regenerative immune microenvironment through bioenergetic activation. Under local mechanical stress, the piezoelectric hydrogel generated piezopotential that initiates osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) via modulating energy metabolism and promoting adenosine triphosphate (ATP) synthesis. Moreover, it also reshapes an anti-inflammatory and pro-regenerative niche through switching M1 macrophages to the M2 phenotype. The synergy of tilapia gelatin and piezoelectric stimulation enhances in situ regeneration in periodontal inflammatory defects of rats. These findings pave a new pathway for treating periodontitis and other immune-related bone defects through piezoelectric stimulation-enabled energy metabolism modulation and immunomodulation.

Immunomodulation has emerged as a promising strategy for promoting bone regeneration. However, designing osteoimmunomodulatory biomaterial that can respond to mechanical stress in the unique microenvironment of alveolar bone under continuous occlusal stress remains a significant challenge. Herein, a wireless piezoelectric stimulation system, namely, piezoelectric hydrogel incorporating BaTiO₃ nanoparticles (BTO NPs), is successfully developed to generate piezoelectric potentials for modulating macrophage reprogramming. The piezoelectric stimulation reprograms macrophages towards the M2 phenotype, which subsequently induces osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RNA sequencing analysis reveals that piezoelectricity‐modulated macrophage M2 polarization is closely associated with metabolic reprogramming, including increased amino acid biosynthesis and fatty acid oxidation. The composite hydrogel with excellent biocompatibility exhibits immunomodulatory and osteoinductive activities. In a rat model of alveolar bone defects, the piezoelectric hydrogel effectively promotes endogenous bone regeneration at the load‐bearing sites. The piezoelectric‐driven osteoimmunomodulation proposed in this study not only broadens understanding of the mechanism underlying piezoelectric biomaterials for tissue regeneration but also provides new insights into the design and development of next‐generation immunomodulatory biomaterials.

Spherical TiO ₂ -NPs permeabilize the BBB most efficiently by inducing cytoskeletal re-organization, and the neurotoxicity of TiO ₂ -NPs appears minimal.