Piezoelectric Tm‐ZnO Nanoparticles Reprogram Neutrophils by Modulating Mitochondrial Homeostasis for Osteoarthritis Therapy

Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory disorder driven by immune dysregulation, with early neutrophil infiltration associated with a pro-inflammatory phenotype and disrupted mitochondrial homeostasis. However, whether restoring neutrophil mitochondrial function can reprogram their inflammatory state and ameliorate OA remains unclear. Distinct from previous piezoelectric strategies for OA that primarily focus on chondrocytes or macrophages, this study focuses on neutrophil mitochondrial immunometabolism. Here, we report piezoelectric thulium-doped zinc oxide (Tm-ZnO) nanoparticles that associate with neutrophil mitochondria to restore mitochondrial homeostasis and reprogram neutrophil polarization. The ultrasmall size and positive surface charge of Tm-ZnO facilitate mitochondrial association, while its enhanced piezoelectric properties (14-fold increase in piezoelectric coefficient) enable activation by low-intensity pulsed ultrasound (LIPUS), generating localized bioelectric cues. This stimulation reduces mitochondrial ROS, enhances oxidative phosphorylation, and is associated with suppression of HIF-1/NF-κB signaling, thereby promoting neutrophil polarization from a pro-inflammatory N1 state toward a reparative N2 phenotype. In vitro and in vivo, Tm-ZnO+LIPUS attenuates synovial inflammation, restores chondrocyte anabolic activity, limits matrix degradation, and facilitates cartilage repair. Together, these findings establish a mitochondria-associated piezoelectric strategy for bioelectric reprogramming of neutrophil immunometabolism and highlight its therapeutic potential for OA and other chronic inflammatory diseases.