Safety, Efficacy and Bio-Distribution Analysis of Exosomes Derived From Human Umbilical Cord Mesenchymal Stem Cells for Effective Treatment of Bronchopulmonary Dysplasia by Intranasal Administration in Mice Model.

PURPOSE: Exosomes (Exos) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) hold great potential for treating bronchopulmonary dysplasia (BPD); however, safety concerns and effects of intranasal administration remain unexplored. This study aimed to explore the safety of hUC-MSCs and Exos and to investigate the efficacy and bio-distribution of repeated intranasal Exos administration in neonatal BPD models. METHODS: Characteristics of hUC-MSCs and Exos were analyzed. A subcutaneous tumor formation assay using a single dose of hUC-MSCs or Exos was conducted in Crl:NU-Foxn1nu mice. Vital signs, biochemical indices, pathological alterations, and (18)F-FDG microPET/CT analysis were examined. Pulmonary pathology, three-dimensional reconstructions, ultrastructural structures, in vivo and ex vivo bio-distribution imaging analyses, enzyme-linked immunoassay assays, and reverse transcription-quantitative polymerase chain reaction analyses of lung tissues were all documented following intranasal Exos administration. RESULTS: Characteristics of hUC-MSCs and Exos satisfied specifications. Crl:NU-Foxn1nu mice did not exhibit overt toxicity or carcinogenicity following a single dose of hUC-MSCs or Exos after 60 days of observation. Repeated intranasal Exos administration effectively alleviated pathological injuries, restored pulmonary ventilation in three-dimensional reconstruction, and recovered endothelial cell layer integrity in ultrastructural analysis. Exos steadily accumulated in lung tissues from postnatal day 1 to 14. Exos also interrupted the epithelial-mesenchymal transition and inflammation reactions in BPD models. CONCLUSION: As a nanoscale, non-cellular therapy, intranasal administration of Exos was an effective, noninvasive treatment for BPD. This approach was free from toxic, tumorigenic risks and repaired alveolar damage while interrupting epithelial-mesenchymal transition and inflammation in neonatal mice with BPD.