Endometrial traumas may cause intrauterine adhesions (IUAs), leading to infertility. Conventional methods in clinic haven’t solved the problem of endometrial regeneration in severe cases. Umbilical cord-derived mesenchymal stem cell (UC-MSC)-based therapies have shown some promising achievements in the treatment of IUAs. However, the limitations of potential tumorigenicity, low infusion and low retention are still controversial and restricted the clinical application of MSCs. In contrast, UC-MSC-derived exosomes exhibit a similar function to their source cells and are expected to overcome these limitations. Therefore, a novel and viable cell-free therapeutic strategy by UC-MSC-derived exosomes was proposed in this study. Here, we designed a construct of exosomes and collagen scaffold (CS/Exos) for endometrial regeneration in a rat endometrium-damage model, and investigated the regeneration mechanism through macrophage immunomodulation. The CS/Exos transplantation potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor α/progesterone receptor, and (iv) restored fertility. Mechanistically, CS/Exos facilitated CD163 M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses in vivo and in vitro. By RNA-seq, miRNAs enriched in exosomes were the main mediator for exosomes-induced macrophage polarization. Overall, we demonstrated that CS/Exos treatment facilitated endometrium regeneration and fertility restoration by immunomodulatory functions of miRNAs. Our research highlights the therapeutic prospects of CS/Exos for the management of IUAs.Copyright © 2020. Published by Elsevier Ltd.