Metabolic-epigenetic nanoregulator attenuates a folate-deficiency-associated senescence phenotype in intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is increasingly recognized as an aging-associated disorder driven in part by nucleus pulposus cell (NPC) senescence, yet the nutrient-sensitive metabolic defects that sustain this state remain poorly understood. Here, we investigated impaired folate-mediated one-carbon metabolism as a metabolic-epigenetic vulnerability in aged and degenerative discs. Multi-omics analysis, including spatial metabolomics, transcriptomic profiling and single-cell analysis, revealed coordinated reductions in folate-associated metabolic activity and methylation-related potential during IVDD. Functionally, folate deprivation induced DNA damage, oxidative stress, impaired cell-cycle progression, mitochondrial dysfunction, extracellular matrix imbalance and a persistent senescence-associated phenotype in NPCs that was only partially attenuated by folate restoration. To target this vulnerability, we engineered FZCA, an albumin-assembled folate/Zn-doped carbon dot nanomedicine that integrates folate replenishment, FOLR1-associated access to NPCs with senescence-associated features and ZnCD-mediated ROS-scavenging nanozyme activity. FZCA preferentially accumulated in NPCs with senescence-associated features through FOLR1-dependent endocytosis, increased folate-one-carbon intermediates, reduced homocysteine-associated stress and improved global 5-mC-associated methylation status. These combined metabolic, epigenetic and redox effects alleviated the low-folate-induced senescence-associated phenotype. In a rat needle puncture-induced IVDD model, local FZCA administration improved local retention of FZCA within the disc, preserved disc height and hydration, maintained matrix integrity and attenuated radiological and histological degeneration with favorable biosafety. Collectively, these findings identify folate-one-carbon metabolic insufficiency as a targetable aging-associated vulnerability in IVDD and provide a proof of concept for a metabolism-centered nanotherapeutic strategy coupling nutrient restoration, redox regulation, and receptor-facilitated delivery.