Traumatic brain injury (TBI) remains a major global health challenge with limited effective treatments. This systematic review documents the significant evolution of mesenchymal stem cell (MSC) therapies from traditional cell transplants to advanced cell-free products and engineered delivery systems. A systematic search was conducted across Web of Science, Embase, and PubMed/Medline for studies published from January 2015 to June 2025, resulting in the inclusion of 80 studies for qualitative synthesis. The review identifies four primary therapeutic mechanisms: reducing inflammation, protecting brain cells, maintaining the blood-brain barrier, and supporting tissue repair/regrowth. This PROSPERO-registered systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Methodological quality and risk-of-bias were rigorously assessed using a multi-tool approach tailored to study design (Cochrane RoB, SYRCLE, NOS/JBI). Recent clinical evidence (e.g. STEMTRA trial) suggests these treatments are safe and can improve function in chronic TBI patients. Despite this, critical research gaps persist in establishing standardized protocols, optimal dosing, and long-term safety data. Emerging trends include (1) shifting toward enhanced exosomes/secretomes, (2) integrating MSCs/derivatives with advanced biomaterials for controlled delivery, (3) exploring alternative MSC sources, and (4) developing combination therapies. With a deepening mechanistic understanding and positive early clinical results, future research must prioritize standardization and personalized treatment plans to accelerate clinical translation.
Keywords: extracellular vesicles/exosomes; mesenchymal stem cell (MSC); neuroregeneration; translational medicine; traumatic brain injury (TBI).