A Challenge-Oriented Review of Delivery Systems for Cell and Gene Therapies in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, a global public health burden for which current pharmacological and surgical treatments provide symptomatic relief but fail to reverse the underlying degenerative process. The uniquely avascular, hypoxic, acidic, and mechanically demanding disc microenvironment poses formidable barriers to the survival and function of therapeutic cells and genes, emphasizing the critical need for bioengineered delivery systems. In this review, we introduce the structure and microenvironment of the intervertebral disc, as well as the molecular mechanisms underlying IVDD. We then provide a critical comparative analysis of delivery platforms, including hydrogels, microspheres, nanoparticles, nanofibrous scaffolds, and viral and non-viral vectors, around five core delivery challenges: mechanical protection, retention and leakage prevention, targeted intracellular delivery, controlled release kinetics, and metabolic support. Furthermore, we examine the fabrication technologies and material considerations that determine platform performance, and we analyze the translational barriers that have impeded clinical adoption, such as the limitations of small-animal models and unresolved cell leakage. Finally, we highlight emerging strategies, including gene-cell combination therapy and endplate preconditioning, to accelerate the clinical translation of precision therapies for IVDD.