Diabetes is an increasingly prevalent chronic metabolic disorder that affects approximately 537 million adults worldwide between the ages of 20 and 79 (Magliano et al., 2021). Diabetic wounds present as frequent and severe complications linked to diabetes, exhibiting prolonged non-healing processes along with elevated disability rates that cause significant patient distress and impose substantial economic burdens. Although there are several clinical treatment options available, such as wound debridement, flap transplantation, growth factor injections, and biomaterial dressings; these existing methods prove insufficient in addressing the issue effectively (Mishra et al., 2017). Wound healing is a dynamic and intricate process, involving hemostasis, inflammation, proliferation, and remodeling. During the initial phase of wound closure, fibroblasts play a pivotal role as the predominant cell type responsible for wound contraction and closure through their abilities in proliferation, migration, myofibroblast differentiation, and extracellular matrix (ECM) protein production. However, impaired fibroblast proliferation and migration capacities caused by islet dysfunction and elevated blood glucose levels present challenges to achieving effective wound healing (Rai et al., 2023). In the later stages of wound healing, there is a decline in myofibroblast numbers; however, elevated glucose levels promote fibroblasts to undergo trans-differentiation into myofibroblasts - a crucial factor in scar formation (Monika et al., 2021). Myofibroblasts demonstrate heightened expression of alpha-smooth muscle actin (α-SMA), thereby promoting collagen synthesis, particularly Col I (Pakshir et al., 2020). Mitigating the adverse impact of high glucose levels on fibroblasts presents a promising therapeutic approach for addressing stubborn diabetic wounds.

Adipose-derived mesenchymal stem cells (ADSCs) are highly versatile pluripotent stem cells known for their robust proliferation and multi-differentiation capabilities. They possess the distinct advantages of abundant reserves, easy accessibility, and minimal trauma, making them invaluable in the fields of regenerative medicine and tissue engineering (Bacakova et al., 2018; Nourian et al., 2019; Rosa et al., 2021). As research advances on ADSCs, a multitude of studies have underscored the crucial significance of exosomes released by ADSCs in shaping therapeutic outcomes (Zhu et al., 2020; Mathiyalagan et al., 2017; Wang et al., 2022). Exosomes, nano-sized vesicles ranging from 40 to 160nm in diameter, encapsulate a diverse repertoire of proteins, lipids, and nucleic acids. These exosomes are secreted intracellularly and through an entogen-fusion-exosome process, they function as mediators for intercellular communication that regulates various cellular functions and biological processes (Kalluri and LeBleu, 2020). Numerous studies have demonstrated the effective regulation of inflammation, promotion of angiogenesis, acceleration of skin cell proliferation and re-epithelialization, as well as governance of collagen remodeling by exosomes from Adipose-derived mesenchymal stem cell (ADSC-Exos). Importantly, ADSC-Exos exhibit enhanced stability, ease of storage, and lower immunogenicity in comparison to ADSC therapy (An et al., 2021).

TGF-β1, also known as transforming growth factor beta 1, is a crucial regulatory factor in the healing process that occurs after acute tissue injury. It exerts its influence on various cells involved in wound healing, orchestrating their activities to promote efficient repair and regeneration. By stimulating cell proliferation, migration, and differentiation, TGF-β1 helps to restore damaged tissues back to their normal state. However, it is important to note that excessive activation of TGF-β1 can have detrimental effects when it occurs due to chronic injury, severe trauma, or infection. In such cases, the normal reparative mechanisms become disrupted and give rise to pathological fibrosis. This condition is characterized by an abnormal accumulation of collagen tissue within the affected organ or tissue. The excessive deposition of collagen fibers leads to structural changes and stiffening of the affected area. Over time, this can impair the proper functioning of organs and tissues involved (Budi et al., 2021). The Smad pathway plays a crucial role in the development and progression of fibrotic diseases. It is widely recognized as a pivotal mediator due to its ability to transmit signals from transforming growth factor-beta 1 (TGF-β1). When TGF-β1 binds to its receptor, it triggers the phosphorylation of Smad2 and Smad3 proteins, leading to their activation. This activation initiates a cascade of events that ultimately result in the excessive production and deposition of extracellular matrix components, such as collagen, leading to tissue scarring and organ dysfunction. The Smad pathway acts as a key regulator in this process by controlling gene expression related to fibrosis. Furthermore, the involvement of the Smad pathway extends beyond fibrotic diseases. It has been implicated in various other pathological conditions including cancer metastasis, immune disorders, and cardiovascular diseases. Its versatility highlights its significance not only in fibrosis but also in broader physiological processes (Hu et al., 2018).

MicroRNAs, which are short endogenous non-coding RNAs ranging from 19 to 25 nucleotides in length, regulate gene expression by either degrading target mRNA or inhibiting its translation (Saliminejad et al., 2019). In recent years, compelling evidence has emerged highlighting the pivotal role of microRNAs in diseases. Extensive research has been conducted on the up-regulated miRNAs in ADSC-EXO, revealing their targeting of genes associated with mitigating cell senescence, aging-related gene expression disorders, and age-related diseases through comprehensive gene ontology analysis (Choi et al., 2018). In addition to their role as epigenetic regulators, microRNAs play a pivotal role in the intricate mechanisms involved in wound healing and skin scarring. These small non-coding RNA molecules intricately participate in various stages of the wound healing process. Multiple studies have demonstrated that microRNAs effectively suppress inflammation, promote angiogenesis, and regulate collagen deposition during wound recovery (Ghafouri-Fard et al., 2021; Wonnacott et al., 2022; Nosalski et al., 2020). Overall, it is evident that microRNAs serve as indispensable orchestrators of multiple aspects of wound healing and skin scarring processes through their regulatory functions on gene expression networks. Further research into this captivating field will undoubtedly unveil more profound insights into their precise roles and potential therapeutic applications for enhancing clinical outcomes associated with cutaneous injuries.

In this study, we identified ADSCs and ADSC-Exos, and examined the effect of ADSC-Exos on wound healing through both in vitro and in vivo experiments. We hypothesized that ADSC-Exos can be enriched by fibroblasts and promote wound healing, alongside the presence of miRNAs within ADSC-Exos that possess the ability to modulate tissue remodeling. Overall, our study may provide a new strategy for the clinical treatment of diabetic wounds.