Abstract: Objective To assess the clinical safety and in vivo metabolic characteristics of mesenchymal stem cell-derived exosomes (MSC-Exo) in order to provide a reference for the clinical translation and sound applications of emerging biological therapeutic agents. Methods The Clinical Trials. gov registry was searched to identify all registered clinical trials related to MSC-Exo. Studies involving safety assessments were summarized and analyzed. The potential relationships between variations in protein quality and the stability and safety of MSC-Exo were investigated. Results With the rapid advancement of regenerative medicine, MSC-Exo, as a key component of cell-free therapy systems, promised wide applications in the treatment of a range of diseases. A total of 67 clinical trials around MSC-Exo were retrieved, 44 of which were focused on safety and involved a number of countries and diseases. As the number of passages increased, changes in the protein quality of MSC-Exo were observed, including loss of critical functional proteins, enrichment of potentially risky proteins, and instability in immunomodulatory functions, which might compromise its therapeutic safety and efficacy. Conclusion Given the limited data on the long-term safety and in vivo metabolic mechanisms of MSC-Exo in current research, it is recommended that long-term follow-up studies be conducted among clinical subjects and an integrated quality control and evaluation system be established for MSC-Exo. Furthermore, post-marketing pharmacovigilance should be strengthened to ensure clinical safety.

Key words: Mesenchymal Stem Cell, Exosomes, Safety, Applied Translation, Risk Assessment, Proteomics