Extracellular vesicles reprogram cytokine signaling and the immune microenvironment in intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) involves matrix failure and communication between disc-resident and infiltrating immune cells. Mechanical, metabolic and inflammatory stress can alter recipient-cell states through extracellular vesicle (EV) communication and soluble cytokine signaling. We review how donor-cell conditions affect EV cargo, how recipient cells respond and how these responses affect disc injury and repair. Among the endogenous EV pathways reviewed, communication between nucleus pulposus (NP) cells and macrophages has the strongest support. Degenerative disc-cell EVs promote inflammatory macrophage responses, while macrophage small EVs reinforce NP-cell senescence, inflammatory secretion and matrix catabolism. A complete feedback loop has not been demonstrated in native human discs. Therapeutic preparations from mesenchymal stromal cells, conditioned macrophages and platelet products can restrain inflammatory signaling and restore autophagy, mitochondrial function and extracellular matrix synthesis in preclinical models. These effects do not establish whole-disc regeneration or clinical pain relief. Evidence that EVs regulate cytokine production or responsiveness is stronger than evidence that cytokines are physically carried by EVs; the latter requires localization and vesicle-dependent functional controls. Clinical development requires reproducible EV identity and purity and potency assays that reflect the proposed mechanism. Sustained local exposure, biodistribution and safety also need evaluation. Structural repair, immune modulation and pain relief should be assessed separately.