Regenerative restoration of chronic obstructive pulmonary disease by human umbilical cord blood small extracellular vesicles

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and morbidity, and the inability of current treatments to repair lung damage creates an urgent need for novel regenerative therapies. Human umbilical cord blood small extracellular vesicles (hUCB-sEV) are enriched with regenerative factors from multiple progenitor cells, demonstrating great potential for COPD treatment. Herein, we integrated patient-derived COPD airway organoids with InSMAR-chip system to assess the efficiency and mechanism of hUCB-sEV in a high-throughput manner. Our COPD organoids recapitulated disease characteristics following severity gradient and our hUCB-sEV isolation pipeline yielded sEV with high purity, homogeneity, consistency and wound-healing related protein profile. These hUCB-sEVs promoted differentiation and reduced collagen and Notch gene expression and restored intercellular communication on COPD organoids without detectable off-target effect. Collectively, this study illustrates the therapeutic potential of hUCB-sEV for COPD, laying solid foundation for their clinical translation.