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Aims/hypothesis: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice., Methods: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed., Results: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45 + inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs., Conclusions: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.