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

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 Ca2 + 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.