Intervertebral disc degeneration (IVDD) is a leading cause of low back pain and disability worldwide, imposing a substantial socioeconomic burden. Current treatments primarily address symptoms without halting disease progression, necessitating the development of regenerative therapies. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach due to their differentiation potential, immunomodulatory properties, and paracrine activity. However, challenges including poor cell survival, immune rejection, and tumorigenic risks have prompted investigation into cell-free alternatives, particularly MSC-derived exosomes (MSC-Exos) and conditioned media. This comprehensive review synthesizes recent advances in MSC-based therapeutics for IVDD, examining molecular mechanisms including inhibition of apoptosis, suppression of oxidative stress and ferroptosis, modulation of inflammation, promotion of extracellular matrix synthesis, and regulation of cellular senescence. We critically evaluate the therapeutic potential of MSC-Exos, which offer advantages of lower immunogenicity, enhanced stability, and targeted delivery of bioactive molecules including miRNAs and proteins. Emerging strategies including microenvironment-educated exosomes, genetically engineered MSCs, smart hydrogel delivery systems, and peptide-functionalized scaffolds are discussed. We address current challenges in clinical translation, including standardization of isolation protocols, dosing optimization, and safety considerations. While numerous preclinical studies demonstrate efficacy and early clinical trials have shown feasibility and initial safety, rigorous phase III trials are needed to confirm clinical benefit. Despite these obstacles, MSC-derived therapeutics represent a paradigm shift in IVDD treatment, offering the potential for disease modification rather than symptomatic management, though this potential remains to be definitively proven in large-scale human studies.
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