Breaking the degenerative triad: Microenvironment reprogramming biomaterials for intervertebral disc regeneration

Intervertebral disc degeneration (IVDD) represents a leading cause of chronic low back pain worldwide, imposing considerable public health and socioeconomic burdens. Current clinical interventions remain largely palliative, unable to reverse the progressive pathological cascade. This cascade is driven by a core self-amplifying triad of oxidative stress, chronic inflammation, and nutrient deprivation within the unique avascular, high-load disc niche, and ultimately progresses to end-stage terminal phenotypes such as biomechanical failure and neurovascular ingrowth. Over recent years, biomaterial-based regenerative strategies have evolved from passive structural fillers toward multifunctional platforms capable of active microenvironmental reprogramming. This review provides a systematic, critical synthesis of state-of-the-art advances in the field, organized within a hierarchical framework spanning immunometabolic modulation of the degenerative niche and targeted delivery of cellular and molecular therapeutics with further elaboration of precision-stratified design and whole-disc tissue engineering. We critically appraise evidence maturity across different strategy classes and dissect disc-specific translational barriers, noting that most candidate platforms remain at preclinical validation stages. Building on this analysis, we outline priority research directions and realistic near-term translational milestones to guide rational development of next-generation regenerative platforms toward durable functional disc repair.