Current status and future prospects of functionalized mesenchymal stem cells for the treatment of spinal cord injury.

Spinal cord injury (SCI) represents a critical neurological disorder characterized by intricate pathophysiological processes. The hostile local environment induced by secondary damage markedly hinders intrinsic neural repair, and currently available therapies exhibit limited clinical effectiveness. Recently, mesenchymal stem cells (MSCs) have attracted considerable attention due to their paracrine-mediated therapeutic properties, including immunoregulatory effects, neurotrophic factor secretion, and promotion of angiogenesis. Nevertheless, conventional transplantation of MSCs encounters substantial obstacles, such as poor cellular viability post-injection, inadequate homing capabilities, and diminished therapeutic outcomes in the unfavorable post-injury microenvironment. Therefore, it is essential to "functionalize" MSCs to enhance their therapeutic potential. This article systematically reviews three major MSC functionalization strategies: biomaterial-based delivery platforms, genetic engineering approaches, and drug or physical synergistic therapies. Preclinical evidence indicates that these strategies can synergistically improve motor function recovery, promote axonal regeneration and myelination, and suppress inflammatory responses. Overall, functionalized MSC therapy shows greater therapeutic promise than traditional cell transplantation. Future studies should prioritize challenges related to safety, standardization, and large-scale production to support clinical translation, and should further explore multimodal functional integration and intelligent, responsive stem cell systems to achieve breakthroughs in SCI treatment. The translational potential of this article: This article presents a multidimensional therapeutic framework that integrates biomaterial-based delivery platforms, genetic engineering modifications, and non-invasive preconditioning methods to synergistically enhance the survival and functionality of transplanted cells within the hostile injury microenvironment. Preclinical evidence demonstrates these approaches effectively promote motor recovery, axonal regeneration, and inflammatory modulation, while preliminary clinical studies confirm their long-term safety and efficacy in improving neurological function. However, clinical translation faces challenges including the long-term safety of gene editing, standardization of treatment protocols, and the efficacy gap between animal models and human applications.