Diabetes mellitus is one of the most common chronic diseases in modern society, leading to several complications and decreased life expectancy.1 The mechanism of diabetes-related wound chronicity has not been fully elucidated. Diabetic wound healing frequently fails to proceed and stalls the inflammation phase, eventually converting into a chronic wound.2 Oxidative stress has been demonstrated to play a vital role in diabetic wounds. Hyperglycemia increases the generation of intercellular reactive oxygen species (ROS), leading to apoptosis and lipid peroxidation.3., 4. Meanwhile, metabolic perturbations reduce the expression of antioxidant enzymes and compounds. Therefore, redox homeostasis is disrupted with decreased antioxidation defense and excessive ROS generation, resulting in oxidative damage and delayed wound healing.5., 6. Certain evidence-based treatments including pharmacological agents, immunomodulator and nanotechnology, have recently been emerged for diabetic wound healing.7 However, robust data and widespread usage of these strategies are still required, and further effort for diabetic wound management is necessary to improve wound healing rate.

The hallmarks of tumor focus on several underlying principles including proliferation, invasion, metastasis and metabolism.8 Remarkably, tumor growth shares an impressive number of parallels with wound healing, such as sustained proliferative signaling, activation of cell invasion and the promotion of inflammation.9 Similar to diabetic wound healing, there is lack of inflammation resolution phase in tumors. The recruitment of inflammatory cells and delivery of growth factors and cytokines are essential in both wound healing and tumor development.10 However, in contrast to diabetic wound, there is still proliferation in tumors despite persistent sign of inflammation.11 Furthermore, angiogenic factors are upregulated in hypoxic and acidic tumor microenvironment (TME) to exacerbate the proangiogenic response.12., 13. For example, the laminin 332 γ2 chain serves as an important regulator of migration during wound healing, is highly expressed in cancer cells.14 Besides, HGF excreted by melanoma cells has been found to accelerate wound healing by promoting the dedifferentiation and motion of epidermal cells.15 These common features support the continuous growth of the tumor and also provide a potential new strategy for treating diabetic wounds.

Recent researches have indicated that tumor-derived extracellular vesicles (EVs) mediate the intercellular communication of TME. EVs from tumor cells manipulate the fate of surrounding cells to promote the tumor development.16 It has been demonstrated that EVs from tumor cells modulate cellular ROS and enhance resistance to oxidative stress to promote angiogenesis and cell migration.17., 18., 19. So far, current researchers mainly focus on the vital role of tumor-derived EVs in tumor progression, while few have examined their function on wound-related cells.20., 21. In fact, the features of tumor-derived EV make it an attractive candidate for diabetic wound healing, since diabetic wounds behave the loss of mentioned features as previously stated.22., 23. In recent years, EVs extracted from tumor tissue have represented an emerging advance. The tumor tissue-derived EVs (tTi-EVs) contain more components from the tumor extracellular matrix and surrounding cells, possessing more authenticity and richness.24 Besides, tTi-EVs are preferred compared with EVs from tumor cells, since the phenotype shifts in long-term cultivation could be avoided.25

There is retained proliferation in tumors despite persistent inflammation. Inspired by the tumor growth, we speculated that tTi-EVs could regulate the proliferation and migration of wound-related cells. It's worth noting that the existing research has recognized the complex drivers in angiogenesis and metabolic rewiring in breast cancer.26 EVs derived from breast cancer have been found to support the tumor process through the metabolic reprogramming of fibroblasts.27 This might suggest the potential of tTi-EVs derived from breast cancer employed them in the chronic diabetic wound. Therefore, this research aimed to evaluate the effects of tTi-EVs derived from breast tumor tissue in diabetic wounds. We extracted tTi-EVs derived from breast tumor tissue and applied in the diabetic wound to measure their effects on proliferation, migration, and reduction of oxidative stress. Considering the promotion of tumor-derived EVs in tumor development, and few pieces of literature have reported the administration of tumor-derived EVs in the cutaneous wound, we also preliminarily tested the biocompatibility of the tTi-EVs.20 Collectively, the present study proves that tTi-EVs are able to suppress oxidative stress and facilitate diabetic wound healing, which puts forward a novel function of tTi-EVs and provides potential treatment for diabetic wounds.