Mastication‐Induced Electrical Stimulation Activates Prg4 ⁺ Chondroprogenitors for Osteoarthritis Therapy

ABSTRACT Osteoarthritis (OA) is a whole‐joint degenerative disease primarily driven by excessive mechanical overloading, yet current therapies fail to harness biomechanical cues to halt cartilage degeneration. Here, we developed mastication‐driven magnesium‐incorporated piezoelectric nanofibers (MagPie) that could convert joint loading into localized electrical stimulation while releasing Mg 2 + to neutralize the acidic microenvironment. Under mechanical stimulation, MagPie promoted chondrocyte anabolism and suppressed inflammation in vitro. In a rat temporomandibular joint OA model induced by overloading, MagPie, coupled with physiological mastication, restored the damaged osteochondral unit. Through single‐cell transcriptomics, an electro‐sensitive Prg4 + chondroprogenitor‐like cell population was identified as a key mediator of cartilage regeneration. Mechanistically, MagPie‐activated Prg4 + cells enhanced anabolic activity via the ECM‐mediated FAK‐PI3K‐Akt axis and ameliorated the arthritic microenvironment by shifting macrophage polarization toward an anti‐inflammatory phenotype. Genetic ablation of Prg4 attenuated the therapeutic efficacy of MagPie. Together, these findings uncover a mechanism of electrosensitive tissue repair and establish a ‘trash‐to‐treasure’ strategy that harnesses joint overloading to activate endogenous regenerative programs for OA therapy.