Sequential Redox Modulation and Metabolic Reprogramming by a Nanozyme–Hydrogel System Ameliorates Intervertebral Disc Degeneration

The pathogenesis of intervertebral disc degeneration (IVDD) involves oxidative stress, chronic inflammation and metabolic dysfunction in nucleus pulposus cells (NPCs). Current biomaterial therapies remain constrained by transient efficacy and insufficient mechanistic precision. Single-cell transcriptomic analysis of human discs highlighted oxidative stress and glycolytic dysregulation in degeneration-associated NPC subsets, motivating a dual redox–metabolic targeting strategy. Here, we engineered a metal-organic framework (MOF)-based nanozyme (p-MCMZ) that integrated superoxide dismutase and catalase mimetic activities with sustained metformin release. Embedded within an injectable, microenvironment-responsive hydrogel (pM-Gel), p-MCMZ enabled targeted intradiscal delivery. Multi-omics and functional analyses revealed the two-phase therapeutic mechanism: initial reactive oxygen species (ROS) scavenging restored mitochondrial function and suppressed inflammatory cascades, while subsequent metformin release activated AMP-activated protein kinase (AMPK), suppressed aberrant glycolysis and lactate accumulation, reduced histone lactylation and ultimately mitigated cellular senescence. In vivo, pM-Gel treatment preserved disc architecture and significantly attenuated disc degeneration. This work presents a spatiotemporally orchestrated nanozyme–hydrogel system that simultaneously targets redox imbalance and metabolic dysregulation, offering a promising strategy for IVDD therapy.