Rebuilding the degenerative disc microenvironment: mesenchymal stem cells, exosomes, and bioengineered scaffolds

Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, yet current clinical interventions remain largely palliative and fail to restore disc structure and function. While mesenchymal stem cells (MSCs), exosomes, and bioengineered scaffolds have emerged as promising regenerative tools, isolated therapeutic applications often fail to overcome the highly hostile IVDD microenvironment-characterized by severe hypoxia, acidosis, and mechanical overload. This review provides a unique perspective by positioning the "cell-material-molecule" cross-integration as the central paradigm for effective disc regeneration. We critically synthesize how smart biomaterials are engineered to physically match and survive the degenerative niche, thereby providing a resilient sanctuary for MSCs. Concurrently, we highlight how engineered MSCs and their cell-free derivatives (exosomes and regulatory RNAs) synergistically dismantle inflammatory cascades and matrix breakdown. Beyond outlining preclinical and clinical advances, this review deeply analyzes persistent translational bottlenecks-such as cell source standardization, large-scale GMP exosome manufacturing, and long-term scaffold biocompatibility. Ultimately, by outlining the convergence of gene editing, responsive biomaterials, and precision delivery, we define a clear roadmap for transitioning IVDD treatment from palliative symptom management to durable, precision regenerative medicine.