Surviving the Nucleus Pulposus Desert: Next-Generation Strategies for Intervertebral Disc Cell Therapy.

Background: Low back pain remains the leading cause of disability worldwide, with intervertebral disc degeneration representing a major biological contributor. Although cell-based therapies have shown promise in preclinical models, clinical translation has yielded modest and inconsistent outcomes. Accumulating evidence suggests that therapeutic failure reflects not only limitations in cell source or differentiation potential, but also the hostile biochemical and biomechanical microenvironment of the degenerative disc. Hypoxia, nutrient deprivation, acidity, lactate accumulation, fibrosis, senescence, inflammation, and abnormal mechanical loading collectively impair cell survival, integration, and long-term function. Method: We performed a comprehensive review of the literature using PubMed, Web of Science, and Google Scholar, with emphasis on studies published between 2020 and 2026. Evidence was critically evaluated to examine advances in cell-based therapies for IVDD, including cell sources, mechanisms of repair, biomaterial-assisted delivery systems, microenvironment-targeted strategies, translational studies, and emerging technologies that enhance regenerative efficacy. Discussion: Current evidence indicates that successful disc regeneration depends not only on selecting an appropriate therapeutic cell source but also on overcoming the biological constraints imposed by the degenerative niche. We critically compare the regenerative potential of mesenchymal stromal cells, nucleus pulposus cells, and induced pluripotent stem cell-derived therapies, highlighting their respective advantages and limitations. We further discuss how biomaterial carriers, extracellular vesicles, developmental biology-guided differentiation, genetic engineering, preconditioning approaches, and smart delivery platforms are being integrated to improve cell survival, phenotype stability, extracellular matrix restoration, and functional repair. Conclusion: Future success in intervertebral disc regeneration will require integrated therapeutic strategies that combine optimized cell sources with biomaterial-assisted delivery, microenvironment modulation, and precision bioengineering. Advancing these complementary approaches will be essential for achieving durable biological repair, restoring disc structure and function, and translating regenerative therapies into effective clinical treatments for patients with degenerative disc disease.