Exosomes and Macrophages: Bidirectional Mutual Regulation in the Treatment of Diabetic Complications

Abstract

Purpose

The bidirectional regulation of macrophages and exosomes provides a meaningful research direction for the treatment of complications arising from both type 1 and type 2 diabetes mellitus. However, there is currently no comprehensive evaluation of the bidirectional regulatory role of macrophages and exosomes in diabetic complications. In this review, we aim to provide the detailed process of the bidirectional regulation mechanism of macrophages and exosomes, and how macrophage-associated exosomes use this mechanism to make it better applied to clinical practice through biotechnology.

Methods

Therefore, we summarized the bidirectional regulation mechanism of macrophages and exosomes and the application based on the bidirectional regulation mechanism from two aspects of inflammation and insulin resistance.

Results

As key regulators of the immune system, macrophages are crucial in the progression of diabetic complications due to their significant impact on the regulation of cellular metabolism, inflammation, and insulin sensitivity. Furthermore, exosomes, as innovative mediators of intercellular communication, transport miRNAs, proteins, and various bioactive molecules, influencing the occurrence and progression of diabetic complications through the regulation of inflammation and insulin resistance. The bidirectional regulation between macrophages and exosomes provides a promising pathway for the treatment of diabetic complications aimed at regulating the immune response and improving insulin sensitivity.

Conclusions

Understanding the complexity of the interaction between macrophages and exosomes can advance the treatment of diabetic complications and drug development, and bringing more innovative and effective treatment strategies for diabetic complications.

Introduction

Diabetes, as an endocrine metabolic disorder, exists in two primary forms: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [1, 2]. Both types share the common characteristic of elevated blood glucose levels. However, persistent hyperglycemia leads to elevated secretion of inflammatory cytokines and reactive oxygen species, increasing oxidative stress both intracellularly and extracellularly. Additionally, hyperglycemia and oxidative stress cause endothelial cell dysfunction, leading to delayed wound healing and the onset of diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic cardiovascular disease, and diabetic foot [3]. In clinical practice, pharmacotherapy remains the primary approach for treating diabetic complications. However, long-term medication use in most patients only delays disease progression and may lead to drug-related side effects such as hypoglycemia, nausea, vomiting, and headaches [4]. Therefore, there is an urgent need to identify new potential targets and therapeutic tools for diabetic complications. The communication networks between cells and organs are essential in the treatment of diabetic complications [5].

Exosomes, as natural nanoparticles, can be released by macrophages and, conversely, can also act on macrophages. This bidirectional regulatory mechanism offers potential advantages in the treatment of diabetic complications [6]. Macrophages participate in intercellular communication and regulation by releasing exosomes carrying bioactive molecules, thereby facilitating information transfer between cells [7]. They can not only regulate diabetes-related inflammatory responses by stimulating the release of inflammatory mediators such as cytokines and chemokines but also release bioactive molecules like miRNAs [8]. These bioactive molecules regulate insulin signaling pathways, influencing insulin sensitivity and improving insulin resistance associated with diabetic complications. Moreover, macrophages regulate their activation states by taking up exosomes from other cells, promoting their polarization towards either classically activated macrophages (M1) or activated macrophages (M2). This process inhibits the inflammatory response of macrophages, alleviates tissue damage and inflammatory diseases associated with diabetes, and aids in the clearance and repair of damaged islets [9]. Consequently, this improves the treatment outcomes for complications such as diabetic nephropathy, diabetic peripheral neuropathy, and diabetic cardiovascular diseases [10–14].

Compared to cell-based therapies, exosome administration offers advantages in precise dosing and targeting. Isolating and purifying exosomes from cell cultures allows for accurate control of the therapeutic product’s dose and composition [15]. Additionally, engineering or modifying exosomes can enhance their targeting specificity to desired tissues or cell types, thereby minimizing off-target effects and reducing the risk of unintended intercellular interactions and associated adverse reactions [16]. Exosome carriers provide substantial benefits for cell-based drug delivery and nanotechnology applications. Incorporating exosomes into drug delivery systems like hydrogels and excipients facilitates effective drug transportation, overcoming diverse biological barriers and mitigating the risk of immunogenicity (Fig. 1) [17]. While numerous studies have explored exosomes about macrophages, there is currently a lack of literature fully elucidating the bidirectional regulatory mechanisms of macrophages and exosomes in complications arising from both T1DM and T2DM. Additionally, preclinical research on this topic remains limited. The primary focus of this article is to review the bidirectional regulatory mechanisms between macrophages and exosomes in complications arising from both T1DM and T2DM. The exploration of how exosomes employ biotechnological methods to address diabetic complications offers fresh insights into strategies for their prevention and management.

Fig. 1.

The preclinical testing process of the exosome drug delivery system. Exosomes (including RNA, DNA, or protein) isolated by are encapsulated in various materials (hydrogel, graphene, microneedle, nanoparticle, 3D-printed scaffold), and act on mouse or rat models of various diabetic complications utilizing injection, subcutaneous implantation, or wound dressing for preclinical research

Exosomes: Biogenesis, Isolation, Composition, and Function

Exosomes originate from the endosomal pathway, initiated by the formation of early endosomes, which subsequently mature into multivesicular bodies (MVBs). Intraluminal vesicles (ILVs) form through the inward budding of the endosomal membrane within the MVB, leading to the encapsulation of cytoplasmic contents within ILVs. MVBs can either fuse with lysosomes for degradation or fuse with the plasma membrane, releasing ILVs as exosomes into the extracellular space [18]. The generated exosomes harbor a diverse array of biomolecules, encompassing various proteins (such as membrane transporters, adhesion molecules, signaling proteins, heat shock proteins, and enzymes involved in various cellular processes), lipids, nucleic acids (including mRNA, miRNA, and other non-coding RNAs), and metabolites [19]. Presently, ultracentrifugation is the predominant technique employed for exosome isolation. Initially, cell culture supernatant is collected and subjected to a pre-clearing step to remove cell debris and nuclei. Subsequently, ultracentrifugation is performed to pellet the exosomes, followed by washing and another round of ultracentrifugation to obtain purified exosomes pellet. Finally, the extracted exosomes are further analyzed, including protein and RNA detection, and stored under appropriate conditions for subsequent experiments (Fig. 2) [20]. Although ultracentrifugation is widely used, it has inherent limitations. Other methods for isolating exosomes, such as ultrafiltration, size exclusion chromatography, immune affinity isolation, polymer-based precipitation, and microfluidic technology are noteworthy alternatives. Researchers can choose the appropriate method based on their specific conditions and requirements (Table 1).

Fig. 2.

Exosome production and isolation. The specific molecules bind to receptors on the cell surface, followed by endocytosis to form early endosomes. These early endosomes migrate within the cytoplasm and gradually mature into late endosomes. During this process, the endosomal membrane invaginates to form intraluminal vesicles (ILVs) within the endosome. Late endosomes, which contain a large number of ILVs, are referred to as multivesicular bodies (MVBs). MVBs are transported through the cytoplasm along microtubules, moving towards the vicinity of the cell membrane. After fusing with the cell membrane, MVBs release the ILVs into the extracellular environment, where they are known as exosomes. Exosomes contain proteins, lipids, and RNA molecules, and they can interact with other cells. In the separation process of exosomes, the precipitate (exosomes) obtained by ultracentrifugation at 100000×g for 70 min can be centrifuged again at 100000×g for 70 min to remove pollutants. Repeat this step twice to ensure the purity of exosomes

Table 1.

Different methods of exosome isolation and their advantages and disadvantages

Isolation method	Advantages	Disadvantages	References
Ultracentrifugation	Commonly used and mature methods, no special reagents required	Time-consuming, large sampling volume, increased risk of vesicle rupture and loss	[21–23]
Ultrafiltration	Easy operation; no need for high-cost equipment; produce highly-purified exosomes	Hamper elution of exosomes	[24–26]
Size exclusion chromatography	Efficient isolation of exosomes of different sizes, gentle handling, not easy to destroy exosomes	Possible sample contamination with lipoproteins	[27, 28]
Immune affinity isolation	Highly specific, selectively capture specific exosome subpopulations	High reagent costs, specific antibodies	[29, 30]
Polymer-based precipitation	Higher yields, acceptable purity, and comparable biophysical properties and biological functions	Non-specific precipitation may be present	[31, 32]
Microfluidic technology	Efficient and fast, handles micro-volume samples, high isolation accuracy	High cost of equipment and technology, specialized operating skills	[33, 34]

Exosomes, as carriers for transferring bioactive molecules between cells, facilitate the exchange of information and signaling molecules, promoting intercellular communication in various physiological processes, and importantly, regulating immune responses [35]. They present antigens, deliver immune-modulatory molecules such as cytokines and anti-inflammatory proteins, and promote immune tolerance or activation. Exosomes regulate the activity of immune cells, modulate the inflammatory microenvironment, and influence the occurrence and progression of inflammatory responses [36, 37]. Exosomes stimulate cell proliferation and migration within damaged tissues, fostering angiogenesis and the formation of new tissue. Consequently, they expedite the repair process of injured tissues [38, 39]. Furthermore, exosomes participate in regulating the body’s metabolic state. They influence the body’s energy balance and metabolic homeostasis by carrying factors that regulate glucose metabolism, lipid metabolism, and protein metabolism [40–42].

The contents and physiological effects of Exosomes may vary slightly between different subtypes. Taking exosomes derived from M1 and M2 macrophages as examples: under activated conditions, M1 and M2 macrophages secrete exosomes containing different types of bioactive molecules. M1 macrophages primarily secrete pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), as well as inducible nitric oxide synthase (iNOS) [43]. Meanwhile, M2 macrophages predominantly secrete anti-inflammatory and reparative factors such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and tissue repair-promoting molecules. These factors modulate immune responses, imparting a more tolerant and reparative phenotype [44]. Because M1 and M2 macrophages exhibit distinct functional characteristics, the exosomes they produce may also possess different functionalities. Exosomes derived from M1 macrophages are inclined towards promoting pro-inflammatory responses and activating immune cells, exacerbating inflammation and tissue damage. They contribute to fibrosis by enhancing fibroblast activation and extracellular matrix deposition, leading to tissue scarring and functional impairment [45]. In contrast, the exosomes derived from M2, exhibit a propensity for inflammation suppression and tissue repair promotion. They facilitate tissue repair and regeneration by inhibiting pro-inflammatory responses, promoting regulatory T-cell differentiation, reducing fibrosis, stimulating angiogenesis, and facilitating tissue remodeling. These findings underscore their immunomodulatory properties [46, 47].

The Pathology and Mechanisms of Diabetic Complications

Each complication has distinct pathological and pathogenic features. In diabetic retinopathy, the thickening and fibrosis of the retinal capillary basement membrane alter vascular wall structure and disrupt retinal hemodynamics, exacerbating the progression of retinal disease [48]. Diabetic nephropathy involves increased deposition of collagen fibers and other extracellular matrix components in the renal tubulointerstitium, forming fibrotic plaques and impairing tubular function and glomerular structure [49]. Diabetic neuropathy sees high glucose and dyslipidemia affecting peripheral nerve cells, including axons, dorsal root ganglia neurons, and Schwann cells, leading to reduced myelinated nerve fiber density and disrupted nerve conduction [50]. Diabetic foot is characterized by pathologic neuropathy, secondary infections, and occlusive arterial disease [51]. Cardiovascular complications in diabetes feature chronic inflammation, procoagulant states, impaired fibrinolysis, aberrant neovascularization, and microvascular deficits, cumulatively altering blood rheology, arterial structure, and endothelial homeostasis [52].

However, these diabetic complications have a common pathological mechanism driven by chronic hyperglycemia. Hyperglycemia induces oxidative stress and chronic inflammation, leading to cellular and tissue damage [53, 54]. The formation of advanced glycation end-products (AGEs), activation of the protein kinase C (PKC) pathway, and increased production of reactive oxygen species (ROS) can disrupt normal cellular signaling and function, contributing to the development of various complications. Additionally, hyperglycemia directly impairs insulin signaling pathways, further exacerbating insulin resistance [55–58].

Recent studies have highlighted that macrophage-derived exosomes and exosomes derived from cells other than macrophages carry regulatory miRNAs, enzymes, and signaling molecules that regulate glucose metabolism, inflammation, and tissue repair [59]. Macrophage-derived exosomes carrying anti-oxidative enzymes and miRNAs reduce oxidative stress and enhance tissue repair, while exosomes from other cells regulate macrophage lipid metabolism and glucose uptake, further contributing to the treatment of diabetic complications. This bidirectional regulation opens new therapeutic avenues, including targeted drug delivery systems [60].

The Bidirectional Regulation of Macrophages and Exosomes and the Gold Standard for the Treatment of Diabetic Complications

Diabetic complications have established gold standards for treatment. These standards are based on systematic, evidence-based guidelines that provide structured and effective treatment strategies aimed at early detection, slowing disease progression, and improving patient outcomes (Table 2) [61]. As shown in Table 2, the establishment of these therapeutic gold standards has commonalities, most of which are related to inflammatory response, glucose metabolism, and angiogenesis. Importantly, both macrophage-derived exosomes and exosomes acting on macrophages are closely related to these mechanisms. Bidirectional regulation of macrophages and exosomes can act on a variety of pathogenic processes and has advantages in inhibiting the onset and progression of diabetic complications [62]. The development of new exosome-centric therapeutic strategies, such as drug delivery using exosomal carriers, could precisely modulate the pathological process of diabetes and its complications while minimizing side effects [63, 64].

Table 2.

Compendium of gold standards for the treatment of diabetic complications

Complication types	Gold standard	Indication	Mechanism	Effect	Side effects	References
Diabetic retinopathy	Anti-VEGF therapy	Proliferative diabetic retinopathy, diabetic macular edema	Inhibits VEGF, reducing neovascularization and macular edema	Reduces vision loss, improves visual acuity	Eye pain, intraocular inflammation, vitreous hemorrhage	[75]
	Laser photocoagulation	Proliferative diabetic retinopathy, severe non-proliferative diabetic retinopathy	Destroys ischemic retinal tissue to prevent neovascularization	Stabilizes retinal structure, prevents vision loss	Eye pain, peripheral vision loss, scarring	[76]
Diabetic nephropathy	Angiotensin converting enzyme inhibitors (ACE inhibitors)	Proteinuria, hypertension	Inhibits angiotensin-converting enzyme, reducing blood pressure and proteinuria	Reduce blood pressure, protects renal function	Hyperkalemia, cough, angioedema	[77]
	Angiotensin receptor blockers (ARBs)	Proteinuria, hypertension	Blocks angiotensin II receptors, reducing blood pressure and proteinuria	Reduce blood pressure, protects renal function	Hyperkalemia, dizziness, kidney dysfunction	[78]
	Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors)	Proteinuria, early diabetic nephropathy	Reduces glucose reabsorption in kidneys, reducing blood sugar and improving renal outcomes	Reduce blood glucose, reduces proteinuria	Genital infections, dehydration, ketoacidosis	[79]
Diabetic neuropathy	Antidepressants	Peripheral neuropathy, pain	Inhibits serotonin and norepinephrine reuptake, modulating pain pathways	Reduces neuropathic pain, improves quality of life	Drowsiness, dizziness, nausea	[80]
	Anticonvulsants	Peripheral neuropathy, pain	Modulates calcium channel function, reducing neuronal excitability	Reduces neuropathic pain, improves sleep quality	Dizziness, weight gain, peripheral edema	[81]
Diabetic foot	Debridement	Ulcers, necrotic tissue	Removes necrotic tissue, promotes wound healing	Enhances wound healing, prevents infection	Pain, bleeding, infection	[82]
	Antibiotics	Infected ulcers, soft tissue infections	Eliminates bacterial infection, reducing inflammation	Resolves infection, prevents spread	Antibiotic resistance, gastrointestinal upset	[83]
	Offloading devices	Pressure ulcers	Redistributes pressure away from ulcers, reducing mechanical stress	Promotes ulcer healing, prevents new ulcers	Discomfort, skin irritation	[84]
Diabetic cardiovascular disease	Statins	Hyperlipidemia, atherosclerosis	Inhibits HMG-CoA reductase, reducing cholesterol levels	Reduce low density lipoprotein cholesterol, reduces cardiovascular risk	Muscle pain, liver enzyme elevation	[85]
	Beta-blockers	Hypertension, heart failure	Blocks β-adrenergic receptors, reducing heart rate and blood pressure	Reduce blood pressure, reduces heart failure symptoms	Fatigue, bradycardia, hypotension	[86]
	ACE inhibitors	Hypertension, heart failure	Inhibits angiotensin-converting enzyme, reducing blood pressure and myocardial workload	Reduce blood pressure, improves heart function	Hyperkalemia, cough, angioedema	[87]

Exosomes associated with macrophages can regulate insulin sensitivity and anti-inflammatory factors, thereby helping to reduce blood glucose levels by improving pancreatic β-cell function and insulin signaling [65, 66]. Furthermore, macrophage-derived exosomes transfer anti-atherosclerotic factors, which reduce cholesterol accumulation and slow the progression of atherosclerosis [67]. Exosomes from adipose tissue or the liver modulate macrophage lipid metabolism, thereby reducing blood lipid levels [68]. Macrophage-derived exosomes carry antioxidant enzymes and antioxidant miRNAs. These exosomes help alleviate oxidative stress by reducing the accumulation of free radicals and oxidative products, thus mitigating cellular and tissue damage [69]. Furthermore, exosomes from other cell types carrying antioxidant factors enhance the antioxidant capacity of macrophages, reducing oxidative stress-induced cellular damage [70]. Macrophage-derived exosomes carry angiogenic and endothelial protective factors that regulate macrophage function to protect endothelial cells, reduce vascular injury, and maintain normal vascular function [71, 72]. Not only, do macrophage-derived exosomes mitigate systemic inflammation by modulating inflammatory signaling pathways, but other cell-derived exosomes influence the polarization state of macrophage, thereby reducing chronic inflammation and improving inflammation-related complications of diabetes [73]. Targeting the bidirectional regulation between macrophages and exosomes allows for the use of exosomes derived from macrophages and other cell types as drug delivery systems [74]. These exosomes deliver anti-inflammatory or regulatory factors directly to macrophages, thereby enhancing the therapeutic efficacy of diabetic complications.

Bidirectional Regulation of Macrophages and Exosomes

The Mechanism of Multiple Macrophage-Derived Exosomes

Exosomes derived from macrophages exhibit anti-inflammatory functions and are pivotal in regulating inflammation during the progression of diabetic complications, thus impacting the treatment of diabetic complications. For example, macrophage-derived exosomes effectively inhibit inflammation by suppressing inflammatory signaling pathways [88]. Additionally, these exosomes significantly accelerate angiogenesis and enhance tissue repair quality, thereby promoting the healing of diabetic wounds. Moreover, macrophage-derived exosomes are instrumental in the treatment of diabetic fracture healing. Exosomes from M2 macrophages stimulate the PI3K/AKT pathway to induce the conversion of M1 macrophages to M2 macrophages, significantly modulating the bone immune microenvironment and thereby accelerating the healing of diabetic fractures [89]. Furthermore, IL-4-polarized human macrophage exosomes (THP1-IL4-exo) influence cellular signaling by linking energy metabolism in target cells to mitochondrial respiration, with the miR-146b-5p within THP1-IL4-Exo capable of reducing Toll-like receptor (TLR)/ nuclear factor-kappa B (NF-κB) signaling in both macrophages and hematopoietic stem and progenitor cells (HSPCs), thereby controlling inflammatory activity and inhibiting the progression of diabetic atherosclerosis. Therefore, THP1-IL4-Exo can be used to control inflammatory outbreaks in cardiac metabolic tissues during obesity-driven diabetes [90]. However, certain macrophage-derived exosomes can have negative effects on the treatment of diabetic complications. High glucose-treated macrophage-derived exosomes (HG-Exo) exacerbate renal damage in diabetic nephropathy, with elevated expression of TGF-β in the kidney contributing to glomerulosclerosis and renal tubular interstitial fibrosis. Simultaneously, HG-Exo can decrease glomerular filtration rate, enhance the expression of inflammatory cytokine iNOS, induce the polarization of pro-inflammatory M1 macrophages, incite the inflammatory response of renal tissue cells, and exert detrimental effects on the treatment of diabetic nephropathy [91]. High glucose-induced macrophage-derived exosomal TGF-β1 mRNA also leads to the overproduction of fibrosis and inflammatory factors, induces mesangial cell proliferation and activation, and promotes mesangial expansion and renal fibrosis [92]. In summary, exosomes derived from macrophages under non-high glucose conditions can alleviate inflammation induced by diabetes through various mechanisms such as inhibiting the release of inflammatory factors, promoting tissue repair, and modulating cellular signaling pathways. This alleviation of inflammation helps mitigate inflammatory reactions and prevents adverse effects during the treatment of diabetic complications, thereby halting disease progression.

Insulin resistance is not only the initiating factor of T2DM but also elevates the risk of diabetic complications. Adipose tissue macrophage-derived exosomal miR-29a is transported to adipocytes, myocytes, and hepatocytes, impairing their glucose uptake. Moreover, it promotes obesity-induced insulin resistance by overacting the target gene PPAR-d. Therefore, targeting the crucial exosomal miR-29a pathway could be considered a novel approach to improve insulin sensitivity, potentially mitigating obesity-induced insulin resistance by inhibiting its production and release [93]. Additionally, obesity may lead to the suppression of MKP5 expression by bone marrow macrophage-derived exosomal miR-143-5p, thereby modulating the insulin signaling pathway in hepatocytes and resulting in insulin resistance [94]. Cytokines IL-4 and IL-13 stimulate bone marrow-derived macrophages to polarize into M2-type macrophages, which secrete exosomes containing miR-690 to promote insulin sensitivity and enhance insulin’s effect on adipocytes and hepatocytes. Exosomal miR-690 can serve as a novel insulin sensitizer and holds the potential for the treatment of diabetes and its complications [95]. Combining rosiglitazone (Rosi) with adipose tissue macrophage-derived small extracellular vesicles (ATM-sEVs) from lean mice can improve glucose intolerance and insulin sensitivity caused by obesity, without causing adverse effects such as weight gain or hemodilution. Rosi-ATM-sEVs miR-690 can directly enhance insulin sensitivity in insulin-responsive tissues. This provides strong support for the potential of M2-type bone marrow-derived macrophage exosomal miR-690 as an insulin sensitizer [96]. Under high glucose conditions, macrophage-derived exosomal MALAT1 inhibits the expression of miR-150-5p, thereby alleviating insulin resistance and reducing lipid accumulation and vascular inflammation. Macrophage-derived exosomes containing MALAT1 could prevent vascular diseases through cell-free therapy, offering a novel approach to the treatment of diabetic vascular complications [97]. Lipotoxicity-polarized macrophage-derived exosomal miR-27-3p not only reduces glucose tolerance and insulin sensitivity but also triggers an NLRP3-dependent pro-inflammatory response driven by prolonged mtROS generation. Persistent lipotoxicity impairs mitophagy, which in turn exacerbates insulin resistance, establishing a harmful feedback loop between mitophagy dysfunction and insulin resistance, which further worsens diabetic complications. MiR-27-3p antagomir can ameliorate insulin resistance in insulin-sensitive tissues, thereby having a positive impact on preventing the progression of diabetic complications [98]. Exosomes derived from macrophages affect insulin sensitivity by carrying inflammatory factors and molecules that regulate intracellular lipid metabolism, thereby contributing to the occurrence and exacerbation of insulin resistance. Therefore, the development of inhibitors targeting specific pathways and signaling mechanisms may become a significant focus of scientific research, aiming to mitigate the impact of macrophage-derived exosomes on insulin resistance (Table 3).

Table 3.

The mechanisms of macrophage-derived exosomes

Action pathway	Source of exosomes	Exosome content	Experimental model	Route of administration	Biological function	Molecular mechanism	Application	References
Inflammation	Macrophages	Exos	Hyperglycemic skin injury SD rat	Subcutaneous injection	Inhibits inflammatory signaling in vivo	TNF-α, IL-6↓	Diabetic wound healing	[88]
	M2 macrophages	M2-Exos	Osteotomized db/db mice (T2DM)	Introduce the fracture site	Macrophages polarized from M1 to M2	PI3K/AKT↑	Diabetic bone wound healing	[89]
	IL-4 polarized human macrophages	MiR-146b-5p, miR-33-5p, miR-21-5p	Apoeh/h Ldlr-/- mice	Intraperitoneal injection	Drive mitochondrial cell signal transduction	TLR/NF-κB↓	Diabetic atherosclerosis	[90]
	High glucose-treated macrophages	HG-treated Raw264.7	High glucose-induced male C57BL/6 mice	Tail vein injection	Glomerulosclerosis and tubulointerstitial fibrosis	TGF-β, TNF-α, IL-1β↑	Aggravate diabetic nephropathy	[91]
	High glucose-treated macrophages	Raw264.7	Male-specific pathogen-free C57BL/6 mice	Tail vein injection	Promote mesangial expansion and renal fibrosis	TGF-β/SMAD3↑	Aggravate diabetic nephropathy	[92]
Insulin resistance	Adipose tissue macrophages	MiR-29a	High fat-induced male C57BL/6 mice	Intravenous injection	Damage insulin sensitivity	PPAR-d↑	Deterioration of condition	[93]
	Bone marrow macrophages	MiR-143-5p	High fat-induced mice	Lipopolysaccharide-induced RAW264.7 exosomes	Regulation of the insulin signaling pathway in hepatocytes results in insulin resistance	MKP5↓	Deterioration of condition	[94]
	M2 bone marrow-derived macrophages	MiR-690	High fat-induced male C57BL/6 mice	Tail vein injection	Promote cell insulin sensitivity	NADK↑	Improve insulin resistance	[95]
	Macrophages containing MALAT1	MALAT1	Male Wistar rat with an intraperitoneal injection of streptozotocin	Intracarotid injection	Reduce balloon injury	MiR-150-5p↓	Diabetic angiopathies	[97]
	Lipotoxicity-polarised macrophages	MiR-27-3p	High fat-induced male C57BL/6 mice	Intravenous injection	Reduce glucose tolerance and insulin sensitivity	MIRO1↓	Deterioration of condition	[98]

The Mechanism of Various Exosomes Acting on Macrophages

Exosomes exert significant therapeutic effects on diabetic complications by modulating macrophage polarization and participating in intercellular signal transduction. For example, Urinary stem cell-derived exosomal circRNA ATG7 promoted M2 macrophage polarization while inhibiting MI macrophage polarization to reduce the release of pro-inflammatory factors and regulated the SOCS1/STAT3 signaling pathway through miR-4500 to attenuate the renal injury in diabetic nephropathy and alleviate the deteriorating trend of diabetic nephropathy [99]. Human umbilical cord mesenchymal stem cells-derived exosomal miR-146a-5p emerged as a crucial contributor to the therapeutic approach to diabetic nephropathy. It regulated the imbalance of M1/M2 macrophages by targeting the TRAF1-STAT2 pathway, promoting M2 macrophage polarization to inhibit renal inflammation in diabetic nephropathy patients, thereby restoring renal function in diabetic nephropathy [100]. Additionally, miRNA-17-3p contained in exosomes derived from human umbilical cord mesenchymal stem cells plays a crucial role in the targeted treatment of diabetic retinopathy. Overexpression of miRNA-17-3p reduces the levels of TNF-α, IL-1β, IL-6, MDA, VEGF, and ROS while enhancing the activity of SOD and GSH-Px. Targeting STAT1 alleviates inflammation and oxidative damage in mice with diabetic retinopathy [101]. Exosomes derived from endometrial mesenchymal stem cell / stromal cell subsets contributed to the treatment of diabetic inflammation. Four commonly found miRNAs (has-miR-320e, has-miR-182-3p, has-miR-378 g, has-let-7e-5p), presented in exosomes derived from a subset of CD146 + endometrial-derived mesenchymal stem/stromal cells, they contributed to the regulation of macrophage polarization, T-cell activation, and the transcription of inflammatory cytokines. This modulation increased the secretion of anti-inflammatory factors, coupled with a decrease in pro-inflammatory molecules. Such exosomes displayed the potential to locally exert therapeutic anti-inflammatory effects by influencing the function of macrophages and peripheral blood monocytes [102]. In addressing inflammation induced by T2DM, pancreatic β-cell-derived exosomal miR-29 targets TRAF3, promoting the release of CXCL10 from β-cells, leading to increase inflammatory response to diabetic complications. Blocking miR-29 could protect β-cells from the harmful effects of these inflammatory mediators [103]. Furthermore, miR-29 can suppress both innate and adaptive immune responses. It interacts with NF-κB, resulting in β-cell dysfunction and exacerbating the progression of T1DM. Consequently, blocking the transport of miR-29 represents a potential therapeutic strategy for preventing diabetes-related inflammation [104]. In summary, exosomes from different sources have slightly different effects on macrophages because of their different contents. These exosomes trigger the anti-inflammatory potential of macrophages through different pathways and affect different types of diabetic complications.

Exosomes acting on macrophages regulate their activity while also modulating insulin signaling pathways and lipid metabolism, significantly impacting insulin resistance. Macrophage exposure to adipocyte-derived exosomes resulted in elevated production of the proinflammatory cytokines, heightened macrophage migration to adipose tissue and liver, and facilitated the development of insulin resistance. Inhibition of TLR4 gene expression prevented the adipose tissue-derived exosomal RBP4 protein from inducing the production of pro-inflammatory cytokine by macrophages in a TLR4-dependent manner, thereby suppressing insulin resistance and relieving diabetic complications [105]. The exosomal microRNA miR-1249-3p, derived from natural killer cells, suppresses the TLR4/NF-κB signaling pathway by facilitating the interaction between SKOR1 and SMAD6. This regulatory mechanism attenuates insulin resistance and inflammation, thereby fostering glucose homeostasis. Consequently, targeting this pathway represents a promising therapeutic strategy for managing diabetic complications [106]. The conditioned medium released by Kupffer cells, loaded with lipotoxic hepatocyte- or circulating-derived exosomes, diminished insulin-induced hepatocyte phosphorylation of AKT. The hepatocyte-macrophage/Kupffer cell-hepatocyte paracrine crosstalk was mediated by hepatocyte or circulating-derived exosomes containing saturated fatty acids. Selective depletion of Kupffer cells has been shown to ameliorate steatosis and insulin resistance. Saturated fatty acids released by hepatocytes constitute crucial components of the cargoes within hepatocyte- or circulating-derived small extracellular vesicles. These cargoes are translocated to macrophages and Kupffer cells, initiating insulin resistance through target genes. Lipotoxic saturated fatty acids encapsulated in hepatocyte or circulating-derived small extracellular vesicles represent potential targets for the treatment of diabetic complications [107]. Additionally, research has shown that adipocyte-derived exosomes carrying Sonic Hedgehog (Shh) stimulate M1 macrophage polarization through the Ptch and PI3K pathways, resulting in insulin resistance in adipocytes. Blocking Shh signaling may be a therapeutic approach to inhibit the development of insulin resistance [108]. In summary, exosomes exert a dual role on macrophages: they can both ameliorate and induce insulin resistance. Blocking the pathways associated with exosome-induced insulin resistance or inhibiting the target genes within these pathways could serve as effective strategies for diabetic complications (Table 4).

Table 4.

The mechanism of various exosomes acting on macrophages

Action pathway	Source of exosomes	Exosome content	Experimental model	Route of administration	Biological function	Molecular mechanism	Application	References
Inflammation	Urinary stem cells	CircRNA ATG7	Diabetic nephropathy rat	Intraperitoneal injection	Inhibit M1 macrophage polarization and promote M2 macrophage polarization	SOCS1↑	Diabetic nephropathy	[99]
	Human umbilical cord mesenchymal stem cells	MiR-146a-5p	Diabetic nephropathy rat	Tail vein injection	Promote M2 macrophage polarization	TRAF6, STAT1↓	Diabetic nephropathy	[100]
	Human umbilical cord mesenchymal stem cells	MiRNA-17-3p	A mouse diabetes model	Injection	Reduce inflammatory factors and reduce oxidative damage	TNF-α, IL-1β, IL-6, MDA, VEGF, ROS↓	Diabetic retinopathy	[101]
	CD146 + endometrial-derived mesenchymal stem/stromal cells	Hsa-miR-320e, hsa-miR-182-3p, hsa-miR-378 g, hsa-let-7e−5p	Human peripheral blood mononuclear cells	THP-1/eMSC Exos and PBMC/eMSC Exos co-culture	Promote M2 macrophage polarization	IL-10, IL-13↑	Diabetes-related inflammation	[102]
	Pancreatic β Cells	MiR-29	β-cell specific miR-29a/b/c transgenic mice, High fat-induced C57BL6/J mice	Intraperitoneal injection	Polarized M1 macrophages	CXCL10↑	Aggravate T2DM	[103]
	Pancreatic β Cells	MiR-29	NOD mice	RNA purification of NOD mice	Increased pro-inflammatory	IFN-γ↓	Aggravate T1DM	[104]
Insulin resistance	Adipose tissue	ObELV	TLR4 knockout mice	Intravenous injection	Inhibition of macrophage activation	IL–6, TNF–α↓	Relief insulin resistance	[105]
	Natural killer cells	MiR-1249-3p	High fat-induced male C57B/6 mice	Tail vein injection	Regulation of the insulin signaling pathway in hepatocytes results in insulin resistance	SKOR1, TLR4/NF-κB↓	Relief insulin resistance and inflammation	[106]
	Hepatocytes	Saturated fatty acid	High fat-induced male C57B/6j mice	Nanoparticle tracking analysis	Activate macrophage proinflammatory response	CCL2, JNK, p38MAPK, p65-NF-κB↑	Deterioration of condition	[107]
	Adipocyte	Sonic hedgehog	3T3-L1 adipocytes and RAW 264.7 macrophages were co-cultured	Lipofectamine method	M1 macrophage polarization	Ptch/PI3K↑	Deterioration of condition	[108]

The Bidirectional Regulation Mechanism of Macrophages and Exosomes

M1 macrophages are crucial inflammatory cells capable of phagocytosing pathogens. However, under hyperglycemic conditions, M1 macrophage polarization induces the secretion of pro-inflammatory cytokines, which intensify cellular inflammation and disrupt insulin signaling pathways, ultimately leading to insulin resistance. Addressing the chronic inflammatory response in diabetic complications necessitates the promotion of M2 macrophage polarization. M2 macrophages release anti-inflammatory cytokines, support angiogenesis, and mitigate insulin resistance [109]. Recent studies have shown that the way in which macrophage-derived exosomes polarize macrophages is affected by glucose concentration. Macrophage-derived exosomes from macrophages treated with 15 mM glucose induce an M2-like phenotype in recipient macrophages, increase the protein levels of major mitochondrial complexes, and elevate IL-6 expression levels, thereby improving insulin sensitivity in the body. Therefore, developing new drugs targeting macrophage-derived exosomes treated with 15 mM glucose holds great potential for the treatment of diabetic complications [110]. The bidirectional regulation between macrophages and exosomes is not limited to macrophage-derived exosomes acting on macrophages. Exosomes derived from other cell types can also act on macrophages to exert therapeutic effects on diabetic complications. To alleviate the chronic inflammatory response caused by diabetic complications, it is also possible to inhibit M1 macrophage polarization. Exosomes derived from bone marrow mesenchymal stem cells mediate miR-25-3p, which not only restricts M1 macrophage polarization but also promotes the conversion of M1 macrophages to M2 macrophages, thereby exerting a reparative effect on cardiac inflammation. It will be instrumental in the treatment of diabetic cardiovascular disease [111]. In addition to inhibiting M1 macrophage polarization, identifying specific targets that can suppress M1 macrophage polarization is also a viable approach for treating diabetic complications. In diabetic nephropathy, exosome-derived miRNA-34a from renal tissue negatively regulates PPARG Coactivator 1 Alpha (PPARGC1A), promoting the activation of M1 macrophages and tubular cell fibrosis. Inhibitors of miRNA-34a can increase PPARGC1A expression, thereby inhibiting M1 macrophage polarization and tubular cell fibrosis, offering a therapeutic strategy for diabetic nephropathy [112].

Treatment of Diabetic Complications

Application of Macrophage-Derived Exosomes

In the treatment of diabetic complications, engineered exosomes demonstrate superior characteristics compared to natural exosomes. These attributes include prolonged circulation, enhanced stability, and targeting capabilities, which effectively aid in drug delivery and release within cells. Engineering of gene-modified M2-like macrophage-derived exosomes through Casein kinase 2 interacting protein-1 (CKIP-1) could be utilized for alveolar bone regeneration under porphyromonas gingivalis (Pg)-dominant inflammatory conditions. CKIP-1 silenced M2-like macrophages transfer exosome Let-7f-5p to cementoblasts, promoting mineralization via targeted activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-dependent mitochondrial biogenesis. This presents a novel therapeutic strategy for the future management of diabetes-induced periodontitis [113]. Ultracentrifugation and cyclic sonication were employed to successfully engineer Melatonin into M2 macrophage-derived exosomes. The released Melatonin from these engineered exosomes promoted macrophage repolarization through immune reprogramming. Furthermore, these engineered exosomes demonstrated the capacity to rescue the osteogenic and cementogenic differentiation abilities of inflammatory human periodontal ligament cells by mitigating excessive endoplasmic reticulum stress and unfolded protein response. Ultimately, Melatonin-engineered M2 macrophage-derived exosomes effectively mitigate the exacerbation of diabetes mellitus, stemming from the decline in anti-infection ability and the increase in inflammatory factors [114]. Compared to synthetic nanoparticles, macrophage-derived exosomes offer advantages such as biocompatibility and resistance to degradation. They can effectively target and deliver exogenous nucleic acids and therapeutic drugs to diabetes-related tissues, thereby accelerating recovery.

Utilizing fusion technology to load exosomes onto biomaterials or employing cell engineering techniques to construct nanosystems carrying specific exosomes can both be used to treat diabetic complications. The F127/tissue-adhesive o-nitrobenzyl alcohol-modified hyaluronic acid (HA-NB) adhesive dual-responsive hydrogel loaded with M2 macrophage-derived exosomes exhibits a dense network structure, tissue adhesiveness, and dual sensitivity to temperature and light. This hydrogel promotes bone healing by facilitating GSK-3β phosphorylation, which activates the Wnt signaling pathway and the β-catenin signaling pathway. Therefore, it holds significant potential for applications in promoting diabetic bone healing [115]. The PANB/Au/AC hydrogel system, utilizing polyallylamine hydrochloride-modified AuNRs as functionalized crosslinking agents, demonstrated outstanding photothermal antibacterial performance under near-infrared radiation, highlighting its advantages in promoting wound healing. The M2 macrophage-derived exosomes incorporated into the PANB/Au/AC hydrogel exhibit sustained and controlled release, effectively suppressing inflammation and eradicating bacterial infections at diabetic wound sites. The integrated hydrogel system effectively accelerates diabetic wound healing by leveraging antibiosis, antioxidant stress, and anti-inflammatory effects [116]. In addition to the hydrogel system described above, a dual-layer microneedle-based wound dressing system has been developed. This system concurrently suppressed inflammation and enhanced angiogenesis at the wound site by encapsulating M2 macrophage-derived exosomes at the needle tip and polydopamine nanoparticles in the backing layer. The exosomes released by this wound dressing system enhance macrophage polarization toward the M2 phenotype. Macrophage exosomes and the photothermal properties of the system work together to inhibit diabetic inflammation and promote angiogenesis in a cell-free manner by up-regulating the expression of CD31 and VWF [117]. Diabetic foot ulcers treatment remains a significant challenge for clinical practitioners. The multifunctional hyaluronic acid hydrogel loaded with M2 macrophage-derived exosomes exhibits excellent self-healing and tissue adhesion properties. This enables rapid hemostasis and, through continuous release of pre-loaded M2 macrophage-derived exosomes, promotes angiogenesis at the wound site, accelerating the healing of diabetic foot ulcers [118]. Moreover, intraperitoneal administration of cationic liposome-assisted lipid nanoparticles enables stable and specific protein expression in insulin-secreting β-cells of the pancreas. The levels of gene transfer facilitated by peritoneal macrophage-derived exosomes aid ionizable lipid nanoparticles in effectively and specifically delivering mRNA to the pancreas. Peritoneal macrophage-derived exosome gene therapy holds promise for treating stubborn pancreatic diseases such as diabetes-related complications (Table 5) [119].

Table 5.

Engineered exosomes and exosome-loaded drug delivery systems

Category	Biomaterials	Exosomes source	Experimental model	Route of administration	Disease	Biological function	References
Macrophage	Genetically engineered exosomes	M2 macrophages	BALB/c nude male mice	Hypodermic implantation	Diabetic periodontitis	CKIP-1↓, PGC-1α↑	[113]
	Melatonin engineered exosomes	M2 Macrophages	Rat ligature periodontitis model	Injection	Diabetic periodontitis	Reduce excessive endoplasmic reticulum stress and unfolded protein response	[114]
	F127/HA-NB-adhesive dual-sensitive hydrogel	M2 Macrophages	Pentobarbital was used to drill holes in the skulls of SD rat	Fill with the bone defect site	Diabetic bone healing	Promote GSK-3β phosphorylation to activate the wnt signaling pathway and β-catenin signaling pathway	[115]
	PANB/Au/AC-hydrogel	M2 Macrophages	Male C57BL/6J mice were intraperitoneally injected with streptozocin	Bond	Diabetic wound healing	Antibiosis, anti-oxidative stress, anti-inflammatory	[116]
	Double-layer microneedle-based wound dressing system	M2 Macrophages	A female SD rat was intraperitoneally injected with streptozocin	Wound dressing	Diabetic wound healing	Improving the expression of CD31 and VWF to promote angiogenesis	[117]
	Multifunctional hyaluronic acid hydrogel	M2 Macrophages	Bleeding liver of mouse	Stent dressing adhered to the bleeding site	Diabetic foot ulcers	Self-healing and tissue adhesion	[118]
	Ionizable lipid nanoparticles	Peritoneal macrophages	C57BL/6 female mice with a small incision along the midline were made with sterile scissors	Syringe filling	Diabetic wound healing	Promote pancreatic mRNA delivery	[119]
Cells other than macrophages	Engineered exosomes	Adipose stem cells	Male C57BL/6 mice were intraperitoneally injected with streptozotocin and two round full-thickness wounds were made with a skin punch	Subcutaneous injection	Diabetic wound healing	Inhibition of p65 and IκBα phosphorylation	[120]
	Engineered exosomes	Mesenchymal stromal cells (miR-146a)	Male BKS.Cg-m + / + Leprdb/J (db/db) mice	Tail vein injection	Diabetic neuropathy	Activation of vascular endothelial cells and change of axonal sensory transduction characteristics	[121]
	Engineered exosomes	Epidermal stem cells (miR-203a-3p)	Two full-thickness wounds were formed on the back of db/db mice using a punch	Intradermal injection	Diabetic wound healing	Activation of JAK2/STAT3 signaling pathway	[122]
	Engineered exosomes	Bone marrow Mesenchymal stromal cells	Female Wistar rat were intraperitoneally injected with streptozotocin	Intramuscular injection	Diabetic neuropathy	Promote pancreatic cell proliferation and inhibit pancreatic β cell apoptosis	[123]
	All-natural hydrogel	Protocatechuic aldehyde hybridized collagen	Application of streptozotocin to Sprague Dawley rat and creation of a whole wound	Hydrogel treatment	Diabetic wound healing	M1 macrophages are transformed into M2 macrophages	[125]
	Graphene oxide-loaded gelatin-alginate hydrogel	Platelet cells	Establishment of chronic full-thickness dorsal skin wounds in diabetic Wistar rat	Local application	Diabetic wound healing	Promote HSP expression and M2 macrophage polarization	[126]
	Injectable hydrogel	Human adipose-derived mesenchymal stem cells	Establishment of round full-thickness wounds in male SD rat diabetic model	Tegaderm film coverage	Diabetic wound healing	Promote M2 macrophage polarization	[127]
	Bioinspired adaptable indwelling microneedle	Mesenchymal stem cells	Diabetic rat model to create a circular full-thickness wound	Skin penetration	Diabetic Ulcers	Inhibit M1 macrophage polarization	[128]
	Electroconductive nerve dressing	Bone marrow stem cells	A diabetic sciatic nerve crush injury model was established in female SD rat	No.25 needle injection	Diabetic neuropathy	Through NF-κB pathway regulates macrophage polarization	[129]

Application of Exosomes from Multiple Sources Acting on Macrophages

Engineered exosomes carrying specific nucleic acids such as siRNA, miRNA, or DNA are delivered to target cells by macrophages, thereby regulating gene expression and playing a significant role in treating inflammatory diseases associated with diabetes. MiR-132 is precisely delivered into adipose-derived stem cell-engineered exosomes, forming miR-132-containing engineered exosomes (miR-132-Exo). MiR-132-exo inhibits the phosphorylation of p65 and IκB along the NF-κB signaling pathway while inducing M2 macrophage polarization, thereby reducing inflammation, accelerating angiogenesis, and promoting collagen remodeling, offering a novel approach to enhancing the speed of diabetic wound healing [120]. Moreover, through the inhibition of the TLR4/NF-κB pathway, engineered mesenchymal stromal cell-derived exosomes, enriched with microRNA-146a, suppress macrophage infiltration and M1 macrophage polarization within the sciatic nerve, consequently mitigating inflammation, diminishing cellular inflammatory factor secretion, and fostering vascular endothelial activation and cytokine production modulation. This intervention significantly enhances nerve conduction velocity, and reduces thresholds for thermal and mechanical stimulation, thus aiding in the amelioration of diabetic neuropathy [121]. Epidermal stem cell-derived exosomes, as potential therapeutic agents, exhibited promising prospects in the realm of engineered exosomes. Specifically, exosomal miR-203a-3p derived from epidermal stem cells orchestrated the regulation of inflammatory responses by downregulating SOCS3 expression in macrophages. This molecular modulation activated the JAK2/STAT3 signaling pathway, ultimately inducing M2 macrophage polarization. The application of miR-203a-3p sensitizer additionally amplified cell regeneration across diverse tissues, ultimately leading to improved diabetic wound healing [122]. The engineered exosomes derived from bone marrow mesenchymal stromal cells (BMSCs), obtained by fusing exosomes originating from BMSCs with liposome-containing polypyrrole nanoparticles (PpyNps), possess antioxidant components that could protect cells in oxidative stress environments. Furthermore, these engineered exosomes promote pancreatic cell proliferation and alleviate hyperglycemia by protecting pancreatic β-cells and enhancing insulin sensitivity, thus facilitating the recovery of damaged nerves in diabetic peripheral neuropathy [123].

Exosome-loaded drug delivery systems primarily achieve precise delivery by transporting exosomes to target macrophages. This approach helps to increase the concentration of exosomes within macrophages, thereby enhancing the therapeutic efficacy for diabetic complications [124]. The physical entanglement network formed by fish gelatin (FG) and protocatechuic aldehyde (PA), along with the chemical crosslinking network formed by photopolymerized methacrylate gelatin (FGMA), constitutes a fully natural hydrogel (FGMA/FG/PA), which exhibits excellent biocompatibility and effective antioxidant properties. The physical closure of wounds reduces external infections, while its chemical antibacterial action and ROS scavenging ability can decrease wound inflammation, demonstrating the significant potential for diabetic wound treatment [125]. The gelatin-alginate hydrogel system loaded with reduced graphene oxide, by incorporating platelet-derived exosomes, inhibits M1 macrophage polarization and promotes M2 macrophage polarization while enhancing the expression of heat shock proteins (HSPs) and activating cellular protective signaling pathways. Near-infrared activation experiments have demonstrated that this multimodal hydrogel can completely close wounds in vivo, showing great potential for the biotherapy of diabetic wounds [126]. Additionally, injectable exosome hydrogels with self-healing properties, composed of chitosan-aniline tetramer (CS-AT) and polyethylene glycol diacrylate (PEG-DA) terminated with benzaldehyde, promote M2 macrophage polarization. They also enhance the proliferation, migration, and tube formation ability of human umbilical vein endothelial cells, accelerating diabetic wound healing [127]. The biomimetic adaptive retention microneedles prepared using a combination of template replication and 3D printing techniques, consist of a tunable polyvinyl alcohol hydrogel needle tip encapsulated with mesenchymal stem cell exosomes and a detachable support base made of 3 M medical tape. The microneedles suppress M1 macrophage polarization, promote cell proliferation, induce angiogenesis and neurogenesis, modulate immune responses, and alleviate inflammation, offering significant value in the care of diabetic complications and tissue engineering [128]. Electroconductive nerve dressings, formulated from a blend of tannic acid and polypyrrole, were laden with exosomes derived from bone marrow stem cells. These exosomes were anchored onto the conductive hydrogel through the establishment of reversible, non-covalent hydrogen bonds, enabling the continuous release and accumulation of exosomes at the site of the lesion. This conductive hydrogel not only exhibited anti-inflammatory effects by regulating macrophage polarization through the NF-κB pathway but also enhanced the regeneration of myelinated axons via the MEK/ERK pathway. As a result, this composite material mitigated diabetes-induced muscle denervation, leading to the restoration of muscle function. The comprehensive impact included an amelioration of diabetic peripheral nerve injury, characterized by enhanced nerve regeneration, recovery of motor function, and alleviation of inflammatory pain [129].

Application of Bidirectional Regulation Mechanism Targeting Macrophages and Exosomes

The bidirectional regulation between macrophages and exosomes holds significant therapeutic potential. Exosomes derived from macrophages and other cell types can serve as efficient drug delivery systems, enhancing the therapeutic effects by directly delivering anti-inflammatory factors or regulatory molecules to macrophages. This approach can improve the treatment of diabetic complications by reducing chronic inflammation and promoting tissue repair. Electrospun scaffolds are engineered by anchoring exosomes derived from reparative M2 macrophages onto nanofiber scaffolds with topologically porous structures. These scaffolds facilitate the release of exosomes, which can be internalized by target cells. Due to the inclusion of exosomes extracted from M2 macrophages, this delivery system not only reduces immunogenicity but also enhances cell migration, tube formation, osteogenic differentiation, and M2 macrophage polarization, thereby promoting diabetic fracture healing [130]. Cell-derived exosomes other than macrophages can also be incorporated into hydrogels to enhance the polarization of M1 macrophages to the M2 phenotype. Incorporating bone marrow-derived mesenchymal stem cell exosomes into carboxyethyl chitosan-dialdehyde carboxymethyl cellulose hydrogels can promote the formation of M2 macrophages and modulate human umbilical vein endothelial cells to enhance angiogenesis. This approach can synergistically regulate the wound inflammatory microenvironment in T1DM rats, thereby restoring the structural integrity and functionality of diabetic skin [131].

Conclusion

The bidirectional regulation of macrophages and exosomes is involved in chronic inflammation, and insulin resistance, which directly affects the progression of diabetic complications. A variety of engineering technical means have been used to optimize the nature and function of exosomes, and a variety of drug delivery systems have been developed to load exosomes, to achieve the loading and delivery of exosomes, and to help deliver exosomes accurately to the target organ to ensure their safety and efficacy in clinical applications. Currently, the quality and quantity of exosomes isolated and purified from cells may be limited [132, 133]. More research should be directed toward the identification and targeted modification of useful components of exosomes. In the future, bidirectional regulation of macrophages and exosomes will hopefully provide strong support for clinical practice, and in-depth exploration in this field is expected to lead to more innovative and effective therapeutic strategies for diabetic complications.

Author Contributions

Xue Li conducted the literature review, drafted the manuscript and visualized the figures. Lianrong Yang formally analyzed and investigated this manuscript. Shujun Xu formally analyzed this manuscript. Yuan Tian was responsible for resources and supervision. Xin Meng revised this manuscript and performed funding acquisition.

Funding

This work was supported by the Science Foundation of Heilongjiang Administration of Traditional Chinese Medicine (Grant No. ZHY18-021).

Data availability

Data will be made available on request.

Declarations

Conflict of interest

The authors have no conflicts of interest associated with this work.