Mesenchymal stem cell-derived secretome in traumatic brain injury: Stage-specific paracrine mechanisms and translational challenges.

Traumatic brain injury (TBI) is a stage-dependent disorder that evolves from acute neuroinflammation, blood-brain barrier (BBB) disruption, oxidative stress, excitotoxicity, and apoptosis to subacute neurovascular remodeling and chronic impairment of neuroregeneration and circuit repair. Current clinical management improves survival by stabilizing physiological status and limiting secondary injury, but it rarely rebuilds damaged neural networks or restores long-term neurological function. Mesenchymal stem cells (MSCs) have therefore attracted attention as regenerative candidates, with increasing evidence indicating that their benefits are mediated mainly by paracrine mechanisms rather than direct neuronal replacement. This review presents the MSC-derived secretome as a multilayered therapeutic system composed of soluble mediators and extracellular vesicles (EVs), the latter serving as carriers of proteins, lipids, messenger RNAs (mRNAs), microRNAs (miRNAs), and other regulatory cargoes. Instead of listing isolated cytokines, growth factors, or chemokines, we organize MSC paracrine mechanisms by TBI stage: acute neuroprotection, subacute vascular and immune remodeling, and chronic neurogenesis, synaptic plasticity, and network repair. We also clarify the relationship between EVs and their cargoes and compare the evidence levels for exosomes, microvesicles, and apoptotic bodies. Finally, we discuss translational barriers, including secretome heterogeneity, therapeutic-window optimization, delivery efficiency, bioengineering approaches, and clinical translation.