This review surveys engineered stem cell approaches (gene editing, biomaterials, pretreatment) for CNS repair, emphasizing paracrine actions—neurotrophic factor secretion, immune modulation, and exosome-mediated cargo delivery—and summarizes preclinical benefits across disorders including…

Offers moderate Parkinson's therapeutic value by cataloging actionable engineering strategies and paracrine mechanisms that could enhance cell-based neuroprotection and circuit repair, but it lacks PD-specific mechanistic insights or clinical validation.

Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.