The progression of intervertebral disc degeneration (IDD) is closely linked to the nucleus pulposus cells (NPCs) senescence driven by oxidative stress and extracellular matrix (ECM) abnormalities. This study presents an ultrasound-responsive, temperature-sensitive piezoelectric hydrogel (TT@P-Gel) that enables dual therapy combining electrical stimulation (ES) and controlled drug release, fabricated by incorporating pyrrole/barium titanate nanoparticles (PB NPs) loaded with tannic acid (TA) and transforming growth factor-β (TGF-β). Experiments have demonstrated that TT@P-Gel can initiate the electrically controlled release of TGF-β and facilitate the gradual TA release to neutralize reactive oxygen species (ROS) via ultrasound in vitro, thereby reducing β-galactosidase expression and restoring the mitochondrial membrane potential ΔΨm in senescent NPCs. Under ultrasound stimulation (US), TT@P-Gel via ES activated the AMPK-FOXO1a signaling pathway and promoted FOXO1a nuclear translocation. Additionally, ES and TA released from the hydrogel enhance SIRT1 expression, which stabilizes nuclear FOXO1a through deacetylation, thereby regulating the expression of downstream genes. Furthermore, TT@P-Gel stimulated the BNIP3-PINK1-Parkin pathway via FOXO1a to augment mitophagy, eliminate defective mitochondria, and counteract TBHP-induced cellular senescence. In vivo investigations indicated that TT@P-Gel combined with ultrasound, markedly enhanced the disc height index and Pfirrmann score while diminishing the expression of p16/p21, a marker of senescence, in a rat model of intervertebral disc degeneration. This study introduces an "electro-chemical synergy" strategy to modulate energy metabolism and mitophagy in senescent NPCs under oxidative stress, utilizing an ultrasound-responsive piezoelectric hydrogel, thereby offering a novel approach for the repair and treatment of intervertebral disc degeneration.
