Mastication-Induced Electrical Stimulation Activates Prg4+ Chondroprogenitors for Osteoarthritis Therapy.

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 Mg2 + 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.