Impaired endometrial function and reduced receptivity remain significant causes of female infertility. Here, a sprayable hydrogel combined with human endometrial organoid extracellular vesicles (HEO-EVs) is developed to enhance uterine function preservation and fertility restoration. The peptide amphiphile hydrogel (labeled CPA) is engineered by conjugating a collagen-binding peptide with glutathione to impart its biocompatible adhesive and antioxidant properties. The therapeutic EVs are isolated and purified from human endometrial organoids that have been stably passaged long-term using a bioreactor-culture system. The resulting HEO-EVs-loaded CPA (CPA@HEO-EVs) rapid gelation, triggered by salt-ion interactions, occurs when the fluid is sprayed onto the uterine lining. The ex vivo studies demonstrate that CPA@HEO-EVs promote cell proliferation, scavenges free radicals, and increases tube formation in human umbilical vein endothelial cells. In vivo experiments further validate that in situ spraying with the CPA@HEO-EVs can promote neovascularization, prevent localized endometrial fibrosis, and effectively enhance fertility in a mouse model of endometrial injury. These findings highlight the promising clinical application of in situ sprayed CPA@HEO-EVs hydrogel for targeted endometrial therapy.
Keywords: endometrial injury; extracellular vesicles; female infertility; human endometrial organoids; spray hydrogel.
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