3D hESC Exosome-Derived Circular RNA hsa_circ_0076798 Inhibits M1 Macrophage Inflammatory Response and Alleviates Liver Fibrosis by Suppressing TNF/NF-κB Pathway Through miR-1184/DICER1 Axis.

Here, we employed human embryonic stem cell spheroid (3D hESCs)-derived exosomes to assess inflammatory responses of macrophages in liver fibrosis, and found that 3D hESC-exosomes promoted the transformation of macrophages from M1 to M2 phenotype in vitro. The transplantation of 3D hESC-exosomes exhibited a notable decrease of pro-inflammatory factors, and significant increase of anti-inflammatory factors, and led to a reduction of CD86+M1 macrophages and an increase of Arg-1+M2 macrophages in the livers of treated fibrotic mice, restricting the advancement of liver fibrosis. hsa_circ_0076798, derived from 3D hESC-exosomes, acts as a molecular sponge that sequesters miR-1184, thereby mitigating miR-1184-mediated repression of DICER1 expression within macrophages. Further investigation revealed that DICER1 ultimately mitigated macrophage inflammation by deactivating TNF/NF-κB signaling pathway. Therefore, our findings demonstrated that 3D hESC-exosomes alleviated inflammatory responses by suppressing TNF/NF-κB pathway through hsa_circ_0076798/miR-1184/DICER1 axis, and offers insights into the targeted treatment of liver fibrosis via exosome-based cell-free therapy.