Biomimetic Hydrogen‐Generating Piezoelectric Hydrogel for Dual Glucose Regulation and Mitophagy Activation in Diabetes‐Induced IVDD

Abstract Glucose metabolic imbalance is central to metabolic disorders like diabetes, while mitochondrial dysfunction‐driven reactive oxygen species (ROS) overproduction worsens disease progression. Traditional therapies primarily focus on regulating glucose levels but fail to restore mitophagy. This shortcoming leads to the accumulation of dysfunctional mitochondria and persistent oxidative stress – a pathological feedback loop that is particularly pronounced in diabetes‐associated intervertebral disc degeneration (IVDD), due to the uniquely enclosed and avascular microenvironment. Inspired by gut microbiota that generates biohydrogen (H₂) from glucose metabolism, an ultrasound‐responsive piezoelectric hydrogel (KGmP) is engineered to concurrently tackle dual pathological hallmarks in energy metabolism disorders: disrupted glucose metabolism and impaired mitophagy, particularly in diabetic IVDD. By integrating potassium sodium niobate (KNN) piezoelectric nanoparticles, the KGmP hydrogel converts ultrasonic mechanical energy into localized piezocatalytic cascades, enabling glucose oxidation (2.8 µM g −1 min −1 ) and sustained H₂ release (2.3 µM min −1 ). Mechanistic studies reveal H₂ activates Adenosine 5'‐monophosphate (AMP)‐activated protein kinase (AMPK) to induce mitophagy, breaking the ROS‐mitochondrial damage cycle. In diabetic IVDD models, KGmP elevated collagen II levels and recovered disc height index to 70% of normal. This “two birds with one stone” biomimetic strategy introduces a novel injectable piezoelectric platform for treating energy metabolic disorders by integrating mechanical energy conversion, metabolic regulation, and organelle rejuvenation.