Stem cell and stem cell-derived extracellular vesicle therapy for traumatic brain injury: mechanisms, engineering and translation.

Traumatic brain injury (TBI) remains a major unmet clinical challenge owing to its complex pathophysiology, profound heterogeneity, and limited regenerative capacity of the adult central nervous system (CNS). Existing therapeutic interventions are largely restricted to supportive management and fail to adequately address the secondary injury cascade characterized by persistent neuroinflammation, oxidative stress, vascular dysfunction, and progressive neurodegeneration. Against this backdrop, stem cell-based therapies have emerged as a rapidly expanding area of regenerative medicine with the potential to modulate multiple pathological processes simultaneously. In this Review, we summarize the therapeutic landscape of stem cell interventions for TBI, encompassing mesenchymal stem cells (MSCs), neural stem cells (NSCs), and cell-free derivatives including extracellular vesicles (EVs) and exosomes. We discuss the mechanistic basis of stem cell-mediated repair, focusing on immune microenvironment remodeling, endogenous neurogenesis, neurovascular restoration, apoptosis regulation, and neural circuit reconstruction. We further examine recent advances in therapeutic engineering, including biomaterial-assisted delivery systems, nanotechnology-enabled platforms, preconditioning paradigms, and multimodal combinatorial strategies designed to overcome limitations associated with cell survival, targeting, and functional integration. Finally, we evaluate the current status of clinical translation and highlight the principal biological, technical, and regulatory challenges that continue to impede therapeutic standardization and large-scale implementation. A deeper understanding of stem cell-microenvironment interactions, coupled with advances in bioengineering and rigorous clinical validation, will be essential for translating regenerative strategies into clinically effective therapies for TBI.