A sono-piezoelectric scaffold prompts disc regeneration by activating Ca2+/CaMKII/Parkin-mediated mitophagy

Mitochondrial dysfunction in nucleus pulposus (NP) cells is a key driver of intervertebral disc degeneration (IDD), leading to metabolic imbalance and cellular senescence. To address this, we developed an injectable "sono-electrical coupling" hydrogel (GBC@PNA) based on a thermosensitive P(NIPAM-AAM) network loaded with gallic acid, barium titanate and carbon nanotubes. Upon ultrasound exposure, the scaffold generates a localized micro-electric field and controllably releases gallic acid. This combined stimulation significantly enhanced the viability of degenerated NP cells, promoted extracellular matrix synthesis, and reduced inflammation and senescence in vitro. Mechanistically, the sono-electrical effect activated intracellular calcium signaling, leading to CaMKII-dependent mitochondrial translocation and phosphorylation of Parkin, thereby restarting PINK1/Parkin-mediated Mitophagy to clear damaged mitochondria and restore energy metabolism. This pathway was systematically validated through transcriptomics, protein interaction and functional inhibition studies. In a rat IDD model, the intervention effectively maintained disc height, improved histology and delayed degeneration, demonstrating good biosafety. This work pioneers a strategy that couples external physical energy with intracellular mitochondrial quality control, offering a novel "sono-electro-chemical" therapy for IDD and a new paradigm for "energy-biology"-based tissue engineering.