Safety evaluation of repeated administration of umbilical cord mesenchymal stem cell-derived exosomes

Mesenchymal stem cell-derived exosomes (MSC-Exos) have shown considerable therapeutic potential in regenerative medicine. However, the biosafety profile of these exosomes following repeated administration has not been adequately characterised, and this knowledge gap continues to hinder clinical translation.

Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) were produced on a xeno-free platform by replacing fetal bovine serum (FBS) with human platelet lysate (hPL). A relatively comprehensive and integrated repeated-dose preclinical biosafety profile assessment was then conducted using polyethylene glycol (PEG)-Liposomes as reference nanovesicles. The assessment included pharmacokinetic and distribution analyses using DiD labelling, haematological cytology testing, quantitative measurement of inflammatory cytokines and chemokines, histopathological scoring, and RNA sequencing.

In this study, the safety assessment revealed that: (1) hucMSC-Exos primarily accumulated in the liver and spleen and exhibited an approximately 4-h circulation time; (2) repeated intravenous administration of hucMSC-Exos for 30 days did not result in overt systemic inflammation, and the evaluated haematological and biochemical parameters remained within the normal range; (3) RNA sequencing showed that hucMSC-Exos avoided immune pathway activation (e.g., IL-17/antigen presentation) triggered by PEG-Liposomes, instead enriching complement-coagulation cascades (e.g., C1qc, C6 upregulation) and metabolic pathways (steroidogenesis, retinol metabolism). Together, these findings suggest that hucMSC-Exos have a favourable biosafety profile in a murine model and support further preclinical evaluation for regenerative medicine applications.

This study suggests that repeated intravenous administration of hucMSC-Exos confers a relatively favourable biosafety profile in a murine model and provides preliminary preclinical evidence for further investigation towards clinical translation.