PF-127 Hydrogel-Delivered hUCMSC-Exosomes Attenuate Endometrial Injury by Inhibiting Epithelial–Mesenchymal Transition

Endometrial injury, often resulting from iatrogenic procedures or infections, can lead to fibrosis, adhesions, and infertility. Current therapies are inadequate for reversing fibrosis or restoring normal function. Mesenchymal stem cell-derived exosomes (MSC-exos) present therapeutic potential; however, their rapid clearance poses a challenge. In this study, a thermosensitive PF-127 hydrogel for sustained intrauterine delivery of human umbilical cord MSC-derived exosomes (PF/127-hUCMSC-exos) was developed, and its efficacy and underlying mechanisms were evaluated in a rat model of ethanol-induced endometrial injury. The PF-127 hydrogel extended the retention of exosomes at the injury site for up to 12 days. Compared with control treatment or hydrogel treatment alone, treatment with PF/127-hUCMSC-exos significantly enhanced endometrial morphology, increased thickness and gland number, reduced collagen deposition, and restored fertility. Mechanistically, hUCMSC-exos inhibited the epithelial‒mesenchymal transition (EMT) process by upregulating E-cadherin and downregulating vimentin and β-catenin. Transcriptomic analysis of exosome-treated primary rat endometrial stromal cells revealed significant enrichment in EMT-related pathways and revealed early growth response 2 (EGR2) as a key downregulated target. hUCMSC-exos significantly decreased both the mRNA and protein levels of EGR2, a transcription factor known to promote fibrosis and EMT. In conclusion, the PF/127-hUCMSC-exos hydrogel effectively repaired endometrial injury and restored fertility by inhibiting EMT, potentially through the downregulation of EGR2, thereby providing a promising cell-free, targeted strategy for endometrial regeneration.