Biomaterials for intervertebral disc regeneration: Niche reprogramming, precision therapeutics, and structural reconstruction.

Intervertebral disc degeneration (IDD) arises from coupled redox imbalance, inflammation, cellular senescence, nutrient limitation, matrix loss, and mechanical failure. Biomaterials can localize therapy within the avascular disc while combining microenvironmental control with structural support. However, many studies still optimize one mechanism or one disc compartment in isolation. We organize current strategies into three interdependent layers. The first is niche reprogramming through redox control, immunomodulation, metabolic rescue, and delivery of extracellular vesicles, cells, genes, or biologics. The second is precision therapeutics through endotype- and stage-matched platform selection, image-guided delivery, and response monitoring. The third is structural reconstruction of the nucleus pulposus, annulus fibrosus, and cartilaginous endplate using compartment-specific hydrogels, fibrous scaffolds, and whole-disc constructs. We critically compare evidence strength, material parameters, animal models, manufacturability, biosafety, regulatory pathways, and clinical applicability. We also propose a dual-axis decision framework that links disease endotype and degeneration stage to treatment choice. Durable regeneration will likely require coordinated control of the pathological niche, patient selection, and compartment-specific mechanics rather than a single universal material. This framework is intended to guide biomaterial design from proof of concept toward clinically relevant restoration of disc function.