The hyperglycemic environment in T2DM directly impairs the proliferation and migration abilities of fibroblasts and keratinocytes through mechanisms such as the polyol pathway, accumulation of advanced glycation end products (AGEs), and mitochondrial oxidative stress. At the same time, the continuous activation of inflammatory signaling pathways, such as nuclear factor kappa-B (NF-κB), leads to chronic and excessive inflammation and inhibits the expression of vascular endothelial growth factor (VEGF), thereby hindering the formation of new blood vessels. These functional dysfunctions collectively result in delayed re-epithelialization and formation of granulation tissue (27).

Multiple studies have confirmed that the exosomes secreted by mesenchymal stem cells (MSCs) extracted from various tissues, such as umbilical cord, placenta, and bone marrow, can significantly promote the healing of diabetic wounds through multiple mechanisms. Exosomes derived from MSCs can promote the upregulation of vascular endothelial growth factor receptor (VEGFR) and angiogenesis through miRNA-21-5p/miR-221-3p and a kinase transforming (AKT)/mitogen-activated protein kinase (MAPK) signaling pathways (28, 29) and also upregulate the expression of endothelial cells (ECs) tubular formation and glucose transporter by influencing the energy metabolism of vascular ECs, including cell survival ability, metabolic activity, oxidative stress, and antioxidant capacity, thereby facilitating vascular formation and glucose metabolism (30). In addition, exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) can also accelerate the healing of diabetic wounds by alleviating oxidative stress damage to ECs, enhancing the regeneration of granulation tissue, and promoting angiogenesis through up-regulating the expression of VEGF and transforming growth factor β-1 (TGFβ-1) (31, 32). Liang et al. reported that exosomes derived from UCMSCs can also promote EC proliferation, migration, and angiogenesis through the miR-20b-5p/Nrf2/VEGFA axis, thereby promoting angiogenesis in diabetic ulcer wounds (33). Another study shows that the inhibitory agents derived from human placental mesenchymal stem cells (hPMSCs) from patients with gestational diabetes mellitus (GDM) can promote the proliferation and angiogenesis of ECs by targeting intercellular cell adhesion molecule-1 (ICAM-1) through miRNA-130b-3p and increase the expression of angiogenesis-related factors (34). To enhance the sustained release and bioavailability of this exosome, Varyani et al. encapsulated the exosomes derived from hPMSCs in a hydrogel. They found that compared with the exosome-only group, the wound contraction rate, new epidermal length, number of fibroblasts and blood vessels, collagen density, and antioxidant factors, including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), in the treatment group were significantly increased (35).

Some studies have also shown that exosomes derived from adipose-derived stem cells (ADSCs) have a significant effect in the treatment of T2DM. In contrast, they can regulate macrophage polarization, anti-inflammatory and anti-apoptotic functions to improve glucose tolerance and insulin sensitivity while conferring immune regulatory functions to ECs by delivering circular Snhg11 (36, 37). In contrast, they can regulate miR-204-3p/ homeodomain-interacting protein kinase 2 (HIPK2) and miR-1248 to promote ECs proliferation, migration, and angiogenesis and upregulate the mRNA and protein levels of pro-angiogenic factors VEGF-A, angiopoietin-1 (Angpt-1), and TGF-β, thereby improving diabetic foot ulcers (38, 39). Song et al. (40) also incorporated it into gelMA hydrogel to form a mixture and found that gelMA-HExo could enhance the migration, proliferation, and vascular regeneration potential of vascular ECs through miR-144-3p/nuclear factor erythroid 2-related factor 2 (NFE2L2)/hypoxia-inducible factor 1-α(HIF1α).

A study by Ji et al. showed that macrophage-derived exosomes induced by AGEs could impair the proliferation, migration, and tube formation of ECs through the miR-22-5p/forkhead box protein P1 (FOXP1) signaling axis, while increasing monocyte adhesion and the release of proinflammatory cytokines. It can be seen that miR-22-5p is a potential therapeutic target for diabetic skin healing, as inhibiting it can release exosomes and fibroblast growth factors, accelerating oxidative diabetic wound healing (41). Platelet-rich plasma (PRP)-derived exosomes encapsulating hydrogels inhibit fibroblast ferroptosis by upregulating FosB expression, resulting in increased cell survival, reduced oxidative stress, and elevated iron levels. At the same time, the expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) are upregulated, thereby accelerating wound healing (42). Since the role of ECs in skin healing is of paramount importance, many researchers are now focusing on exosomes derived from these. They reported that exosomes derived from ECs can accelerate the healing of skin wounds in diabetic mice by promoting the expression levels of miRNA-221-3p, VEGF, CD31, and Ki67, which are vascularization-related factors and cell proliferation markers. Bioinformatics analysis indicated that miRNA-221-3p may be involved in the Advanced Glycation End product–Receptor for AGE (AGE–RAGE) signaling pathway in diabetes complications, as well as the cell cycle and p53 signaling pathways (43). Furthermore, in exosomes derived from ECs, they reprogram DNA methyltransferase 1 by promoting the expression of endothelial nitric oxide synthase (eNOS), hCAT-1, VEGF, and ICAM-1, thereby reducing the expression of exosome proteins related to vascular complications, such as Thrombospondin1, Pentraxin3, and Cystatin C (44, 45). Exosomes derived from hypoxic urine-derived stem cells and fibroblast stem cells negatively regulate the HIF-1α/VEGF/VEGFR signaling pathway through miR-486-5p and miRNA-24-3p, thereby promoting the proliferation, migration, and tubal formation of ECs (46, 47).

In recent years, engineered exosomes have gained attention due to their customization. Zhai et al. discovered that engineered exosomes containing interleukin-4 (IL-4) have a significant synergistic effect in regulating immune responses and enhancing angiogenesis. In contrast, they can increase the survival rate, migration, and tubule formation ability of endothelial cells (HUVECs), and, in contrast, they can cause macrophages to polarize toward the anti-inflammatory M2 phenotype, achieving complete repair of diabetic wounds (48). Plant-derived exosomes, due to their excellent biocompatibility and stability, can serve as potential therapeutic agents. Studies have found that mango–ginger-derived plant-derived nanovesicles (MGDNVs) can significantly promote keratinocyte migration in vitro and in vivo by inducing the expression of proteins similar to follicular protein 1 (FSTL1). It can be seen that FSTL1 is a key factor promoting migration in wound healing. The study confirmed that MGDNV can become a natural and cost-effective local alternative to traditional biological agents for the treatment of chronic wounds (49).

Exosomes, as nanoscale messengers between cells, play a crucial role in regulating the healing process of diabetic skin wounds by delivering various bioactive substances, as shown in Table 1. Their inherent advantages, such as low immunogenicity, high stability, and ease of storage and transportation, make them a highly promising new therapeutic strategy.

Insulin resistance leads to fatty degeneration of the liver. High insulin and blood sugar levels enhance lipid synthesis and uptake in the liver, while inhibiting fatty acid oxidation, resulting in abnormal fat accumulation within liver cells and the development of non-alcoholic fatty liver disease. Additionally, chronic high blood sugar triggers oxidative stress and endoplasmic reticulum stress, driving inflammatory responses and activation of hepatic stellate cells, which jointly exacerbate liver inflammation and fibrosis (50).

Studies have shown that exosomes derived from bone marrow macrophages (BMMs) can alleviate insulin resistance in hepatocytes and enhance insulin sensitivity through miR-143-5p and miR204/Elovl6. Meanwhile, miR204-mediated interactions between adipocytes and macrophages can regulate insulin sensitivity in adipocytes (51). The exosomes secreted by ADSCs from high-sugar diet sources promote inflammation in adipocytes by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) expression and increase the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome-related proteins (52), while the exosomes secreted by aADSCs from high-fat diet sources induce the formation of non-alcoholic fatty liver disease, lipid accumulation and inflammation (53), from which can be seen that the exosomes derived from ADSCs play a significant role in regulating liver lipid metabolism. In recent years, plant-derived exosomes have been increasingly reported. Lipid-derived exosome-like nanovesicles that are derived from orange peels can alleviate liver steatosis in T2DM by regulating lipid metabolism and the intestinal microbiota (54). Natural exosomes-like nanoparticles in mung bean (MELN) sprouts can alleviate the progression of T2DM by activating the phosphatidylinositol 3-kinase (PI3K)/Akt/glucose transporter type 4 (GLUT4)/glycogen synthase kinase-3β (GSK-3β) signaling pathway, which reduces fasting blood glucose levels, triglycerides (TG), total cholesterol (TC) and reduces the inflammatory infiltration and oxidative stress levels in liver cells, thereby improving the survival ability of liver cells (55). Dual-Carriers of Tartary Buckwheat-Derived Exosome-Like Nanovesicles (TB-ELNs) can regulate glucose metabolism in the gut-liver axis and enhance the phagocytic function of the endoplasmic reticulum, thereby reducing damage to the gastrointestinal tract (56). Exosomes derived from liver and milk can, respectively, inhibit PHLPP2 and the mammalian target of rapamycin (mTOR) in adipocytes through miR-130a-3p and miR-101-3p, thereby alleviating glucose tolerance, demonstrating that they are key players in the body's energy homeostasis (57, 58). A clinical study conducted in 2022 demonstrated that by using a mass spectrometry-based method to analyze the global proteome and phosphorylated proteome of exosomes in patients with prediabetes and T2DM, the results showed that the circulating exosomes in diabetic patients contained higher levels of specific phosphorylated kinases, such as protein kinase b-alpha (AKT1), glycogen synthase kinase 3β (GSK3B), LYN, mitogen-activated protein kinase 2 (MAP2K2), myosin light chain kinase (MYLK_, and Protein Kinase C Delta (PRKCD). Moreover, the activated kinase system may be systematically distributed throughout the body, which provides new insights into the pathobiology of T2DM (59).

Exosomes, as key carriers of intercellular communication, have shown great potential in the treatment of liver diseases in T2DM, as shown in Table 2. By carrying specific miRNAs, proteins, they precisely regulate the fate of liver cells, providing novel strategies for drug delivery and liver disease intervention. Their efficacy has been confirmed in disease models, including fatty liver and liver fibrosis.

The core mechanisms underlying pancreatic lesions in T2DM are the progressive β-cell failure and the formation of pancreatic amyloidosis. In the context of insulin resistance, β-cells undergo compensatory proliferation and secrete excessive insulin, eventually leading to increased endoplasmic reticulum stress and oxidative stress. Lipotoxicity and glycolipotoxicity jointly induce β-cell apoptosis, while abnormal deposition of pancreatic amylin forms pancreatic amyloid substances, further damaging the pancreatic structure (60). This vicious cycle ultimately results in a reduction in β-cell numbers and insulin secretion defects, leading to irreversible pathological changes.

Exosomes derived from MSCs, in contrast, protect β-cells from hypoxia-induced apoptosis and alleviate endoplasmic reticulum stress by regulating miR-21 and inhibiting p38 MAPK phosphorylation, significantly increasing the survival rate of β-cells (61) and, in contrast, they enhance the function and quantity of β-cells, as well as reduce random blood glucose levels, improve glucose and insulin tolerance, and increase insulin secretion, which mechanism is achieved through AKT/extracellular signal-regulated kinase (ERK) (62). Furthermore, multiple studies have shown that some miRNAs play a crucial role in protecting the pancreas. Exosomes derived from ADSCs protect β-cells function by carrying miR-138-5p and regulating the sex-determining region Y (SRY)-box transcription factor 4 (SOX4)-mediated Wnt/β-catenin pathway (63), exosomes derived from M1 macrophages inhibit β-cell insulin secretion by targeting sirtuin 2 (SIRT2) with miR-212-5p and inhibiting the Akt/GSK-3β/β-catenin pathway (64) and Pancreatic cancer-derived exosomes inhibit β-cell function and reduce insulin secretion by targeting adenylate cyclase 1 (ADCY1) and exchange protein directly activated by cAMP 2 (EPAC2) (65). Besides, exosomes derived from liver and muscle can respectively alleviate β-cell damage through AKT kinase and mTOR signaling pathways, significantly increasing their cell survival rate (66, 67).

Exosomes offer innovative therapeutic ideas for pancreatic lesions in T2DM, as shown in Table 3. These natural nanovesicles can precisely improve the function of pancreatic β-cells by delivering active components, such as miRNAs. This therapy, based on intercellular communication, can reshape the pancreatic microenvironment, opening a new therapeutic pathway to prevent the progressive failure of β-cells and reverse the progression of diabetes.

T2DM primarily causes kidney damage through metabolic and hemodynamic pathways. Long-term high blood sugar leads to the accumulation of AGEs, activation of protein kinase C, and hyperactivity of the polyol pathway, all of which jointly cause damage to the glomerular filtration barrier. At the same time, high blood sugar, in conjunction with hypertension, causes high intra-glomerular pressure and hyperfiltration, continuously activating the renin-angiotensin system, promoting inflammatory responses and fibrosis processes, ultimately leading to glomerular sclerosis and tubulointerstitial fibrosis and gradually developing into diabetic nephropathy (68).

Exosomes derived from MSCs can not only induce autophagy in glomerular endothelial cells through the mammalian target of rapamycin (mTOR) signaling pathway to improve DN (69), but also inhibit pyroptosis in proximal tubular cells of the kidney through miR-30e-5p (70), which is the first time the role of exosomes in inhibiting cell pyroptosis in T2DM has been reported. Furthermore, the exosomes derived from BMSCs alleviate DN in rats by inhibiting cell apoptosis and reducing inflammatory levels. The results of the in vivo experiments showed a significant decrease in the levels of glucose (GLU), creatinine (Cr), and blood urea nitrogen (BUN) (71). Ning et al. reported that exosomes derived from glomerular ECs themselves can also carry miR-30a-5p and regulate angiogenesis through the Notch1/VEGF signaling pathway (72). These findings suggest that exosome miR-30-5p may become a potential strategy for treating DN. Besides MSC-derived exosomes, exosomes secreted by ADSCs can also inhibit podocyte apoptosis and slow down DR by activating autophagy flux (73, 74). Studies have confirmed that the expression of miRNA-615-3p and miRNA-3147 in urine-derived exosomes is closely related to the inflammation and fibrosis of DN and is positively correlated with serum cystatin C, plasma TGF-β1, creatinine, blood urea nitrogen (BUN), protein creatinine ratio (PCR), and 24-h urine protein, and negatively correlated with eGFR and albumin (75).

In conclusion, exosomes demonstrate multi-dimensional therapeutic potential in the intervention of DR, as shown in Table 4. They can simultaneously regulate multiple pathological processes of the renal microenvironment: not only inhibiting the release of inflammatory factors and oxidative stress damage, but also maintaining the structural integrity of podocytes and blocking the activation of renal fibrosis signaling pathways. Their natural targeting properties and low immunogenicity offer new avenues for the precise treatment of diabetic nephropathy, especially their unique advantage in delaying glomerular sclerosis and improving renal function indicators.

In contrast, persistent hyperglycemia leads to activation of the polyol pathway, accumulation of advanced glycation end products, activation of the protein kinase C pathway, and oxidative stress response, all of which jointly cause metabolic disorders in neurons and Schwann cells. In contrast, high blood sugar damages microvessels, resulting in narrowing and ischemia of nerve-feeding vessels. These pathological changes ultimately lead to demyelination of peripheral nerve fibers and axonal degeneration, triggering the typical diabetic peripheral neuropathy (76).

The exosomes secreted by BMSCs can exert neuroprotective functions through multiple pathways. First, they can enhance neural conduction velocity and increase the number of epineural nerve fibers (IENFs), myelin thickness, and axon diameter in the sciatic nerve by targeting miRNAs through the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway, and can also reduce and increase the markers of M1 and M2 macrophage phenotypes (77). Second, they can target and weaken the neurological dysfunction after diabetic cerebral hemorrhage through miR-129-5p, promoting neuroinflammation and functional recovery (78). Third, these exosomes can be transferred to the damaged neuronal and astrocyte regions to improve cognitive impairment caused by diabetes and restore normality (79). Additionally, a clinical study derived from adipose tissue exosomes shows that through Mendelian randomization and multicenter population studies, it was confirmed that 13 exosomal miRNAs were significantly upregulated in the adipose tissue of T2DM patients, among which the increase of miR-125a-5p was associated with Alzheimer's disease (AD), risk of amnestic mild cognitive impairment (aMCI) and reduced volume of the left hippocampus. This confirmed that the serum exosomal miR-125a-5p extracted from adipose tissue can serve as a pathogenic biomarker for cognitive impairment in T2DM patients (80).

Exosomes precisely target the core pathological links of neurological disorders regarding T2DM through multiple mechanisms, including regulating neuroinflammation, promoting synaptic remodeling, and clearing abnormal protein aggregates, as shown in Table 5. This intercellular communication carrier provides a new strategy to break through traditional treatment bottlenecks and has significant application prospects in neural regeneration and functional recovery.

In patients with T2DM, elevated blood sugar and the accumulation of AGEs directly inhibit the function of osteoblasts and reduce bone quality. At the same time, inflammatory factors released during chronic inflammation further disrupt the balance between bone formation and bone resorption. Moreover, the combined effects of insulin resistance and oxidative stress interfere with the normal metabolism and repair capabilities of the bones, resulting in reduced bone formation, increased bone fragility, and significantly delaying the bone regeneration process (81).

In terms of bone loss, exosomes derived from damaged liver tissues are significantly enriched in the periodontal region, inducing pyroptosis in periodontal ligament cells (PDLCs). Among them, fatty acid synthase (Fasn) leads to the ectopic synthesis of fatty acids in PDLCs and activates the cleavage of gasdermin D. The results show that the deletion of Fasn in the liver can effectively alleviate the pyroptosis of PDLCs and reduce bone loss. This study reveals the organ communication mediated by exosomes in the “liver-bone” axis, providing insights for the prevention and treatment of diabetes-related bone diseases in the future (26). Salivary exosomes can inhibit local inflammatory responses through miR-25-3p, reducing periodontal alveolar bone loss by approximately 34% (82). In terms of osteogenesis, Schwann cell-derived exosomes improve bone parameters around dental implants in T2DM rats through the miR-15b-5p/Txnip signaling axis (83), BMSC-derived exosomes promote bone regeneration by regulating the miR-17-5p/mothers against decapentaplegic homolog 7 (SMAD7) axis (84) and stem cell exosomes overexpressing Smpd3 promote osteogenesis and differentiation of BMSCs derived from the jawbone by activating jawbone autophagy and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations (85), which collectively provide insights into the molecular mechanism of peripheral nerve regulation of bone regeneration in diabetic patients.

Exosomes, as a key medium for intercellular communication, have shown crucial potential in treating diabetic osteogenic dysplasia, as shown in Table 6. In contrast, they promote the proliferation and differentiation of osteoblasts and enhance their mineralization function. In contrast, they inhibit the activity of osteoclasts. This multi-targeted mechanism can effectively improve microcirculation disorders and inflammatory states in the context of high blood sugar, providing a novel therapeutic strategy for reversing bone loss and accelerating bone defect repair.

Exosomes also have therapeutic effects on other physiological organ complications. Due to the limited research available, we will present these together. Regarding Diabetic cardiomyopathy (DCM), Lin et al. confirmed that exosomes derived from macrophages improve the formation of resistance proteins and neointimal hyperplasia through miRNA-150-5p, exerting a protective effect on the heart (86). However, Govindappa believes that macrophage exosomes significantly enhance the inflammatory and pro-fibrotic responses of mouse fibroblasts and myocardial fibrosis. Only by knocking down human antigen R (HuR) in the exosomes can the angiotensin II-induced myocardialization response be inhibited and the left ventricular function be maintained (87). A clinical study stated that they isolated serum exosomes from 147 patients with and without diabetes and found that CD14 from serum exosomes was associated with T2DM. T2DM may promote the increase of CD14 protein in exosomes, thereby increasing the susceptibility to atherosclerosis. However, the analysis of the contents of exosomes from diabetic patients is still in its early stage, so a comprehensive characterization is crucial for it to serve as a biomarker or to analyze its potential contribution to diabetic complications (88).

Exosomes also exert a promising effect against DR. Exosomes derived from MSCs carry miR-125a-5p, in contrast, they enhance the survival rate, proliferation and migration of corneal ECs. In contrast, they inhibit the endoplasmic reticulum stress induced by high glucose, thereby jointly improving diabetic keratopathy (DK) (89). Additionally, exosomes derived from adipocytes regulate the levels of apoptosis, inflammation, and oxidative stress in mouse retinal microvascular endothelial cells (mRMECs) by modulating the miR-361-5p/TRAF3 axis, making them a potential target for treating microvascular complications induced by diabetes (90). Exosomes derived from Müller cells regulate microglial cell polarization in DR by carrying lncRNAs, including miR-320-3p, miR-221-3p, and miR-574-5p, promoting the polarization of microglia to the M1 phenotype (91).

Furthermore, adipocyte exosomes carry miR-4472, which downregulates the expression level of myocyte enhancer factor 2D (MEF2D), inhibiting the glucose consumption and uptake capacity of skeletal muscle cells (92). Garlic-like exosome-like nanoparticles (GaELNs) increase the level of phosphatidylcholine through the gut–brain axis, inhibiting cGas and STING-mediated inflammation as well as the interaction between GLP-1R and the insulin pathway (93). MSCs-derived exosomes alleviate the damage of human pulmonary microvascular endothelial cells (hPMECs) induced by high glucose and lipopolysaccharide through the Nrf2/heme oxygenase 1 (HO-1) pathway, reducing the levels of inflammation and ferroptosis (94).

Therefore, exosomes derived from different cell sources also play certain therapeutic roles in the heart, lungs, retina, skeletal muscle, and intestinal microbiota, as shown in Table 7. However, current research in these areas is relatively limited. In the future, more studies can be conducted to further explore their mechanism of action.

Exosomes, as a key medium for intercellular communication, have shown great potential in the treatment of multiple systemic complications of T2DM, as shown in Figure 4. These natural nanovesicles can precisely regulate multiple physiological system complications and organs across different tissues. Their unique natural targeting ability and low immunogenicity enable exosomes to act on multiple pathological processes simultaneously, breaking through the limitations of traditional single-target drugs. This treatment strategy, based on intercellular communication, offers a new idea for the collaborative management of T2DM complications and is expected to become an important breakthrough direction in the management of diabetes that involves multiple systems.