Ultrasound‐Activatable Piezoelectric Hydrogel Reprograms Mitochondrial Epigenetics for Osteoarthritis Therapy via the mTOR/GATD3A Axis

ABSTRACT The avascular nature of cartilage hinders drug delivery for osteoarthritis (OA) therapy. We engineered a biomimetic piezoelectric hydrogel (CMB Gel) by embedding chondrocyte membrane‐camouflaged, CAP peptide‐grafted barium titanate nanoparticles into a dynamic borate ester‐crosslinked network, enabling active cartilage targeting and on‐demand ultrasound activation. Under ultrasound, the piezoelectric component generates local electrical signals, triggering Ca ^{2 +} influx via voltage‐gated calcium channels and AMPK activation. Activated AMPK inhibits the mTOR pathway, inducing epigenetic reprogramming via H3K27 acetylation at the GATD3A promoter. Upregulated GATD3A stabilizes TFAM and enhances PINK1/Parkin‐mediated mitophagy, clearing damaged mitochondria and reducing oxidative stress in chondrocytes. In a mouse destabilization of medial meniscus model, ultrasound‐activated CMB Gel attenuated cartilage degradation, osteophyte formation, and synovitis. Its therapeutic efficacy was validated in human OA cartilage explants. This work presents a multifunctional targeted delivery platform that converts mechanical energy into epigenetic signals to restore cellular homeostasis, offering a promising strategy for OA and other mechanosensitive degenerative diseases.