Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing

Table 1 Exosomes have therapeutic potential in inflammatory diseases and enhance wound healing

Pathology	Source of exosome	Outcome
Inflammatory diseases[44]	Adipose-derived mesenchymal stem cells	Exosomes displayed an inhibitory effect in the activation, differentiation, and proliferation of T-cells and inhibit IFN-γ release
Impaired wound healing in diabetes[45]	Whole blood serum	Serum-derived exosomes promoted angiogenesis and extracellular matrix formation
Diabetic wound healing[46]	Bone marrow and adipose tissue	In mice models, adipose tissue-derived EVs promoted wound healing while those that were bone-derived did not
Diabetic wound healing[47]	Macrophages	Macrophage-derived exosomes inhibited the secretion of pro-inflammatory enzymes and cytokines in a rat model
Diabetic wounds[48]	Human umbilical cord mesenchymal stem cells	Exosomes accelerated cutaneous wound healing and reduced the effects of oxidative stress and promoted angiogenesis
Diabetic wounds[49]	Human amniotic epithelial cells	Exosomes promoted angiogenesis and fibroblast function via activation of the PI3K-Akt-mTOR pathway

IFN: Interferon; EVs: Extracellular vesicles; PI3K: Phosphatidylinositol-3-kinase; mTOR: Mechanistic target of rapamycin.

Table 2 Strategies to enhance stability and bioavailability of exosomes

Pathology	Exosomes modification	Source of exosomes	Strategy and outcomes
Impaired diabetic wound healing[13]	MiR-20b-5p-upregulated exosomes	Isolated from diabetic and non-diabetic patient blood	Exosomes derived from diabetics delayed wound healing and angiogenesis compared to exosomes sourced from non-diabetic patients in mice wounds
Diabetic foot ulcer[15]	Nrf2-rich exosomes	ADSCs (human and rat)	Increased granulation tissue formation, angiogenesis, and growth factor levels and reduced levels of inflammation and oxidative stress with exosomes in a rat model
Diabetic wound[55]	Pioglitazone pre-treated exosomes	MSCs	PGZ-treated exosomes promoted angiogenesis and enhanced wound healing in a rat model
Diabetic foot ulcers[56]	LncRNA H19-overexpressed exosomes	MSCs	LncRNA h19-rich exosomes prevented apoptosis and inflammation of fibroblasts and stimulated wound healing in the mice model
Diabetic wounds[57]	Deferoxamine preconditioned exosomes	Human bone marrow	The preconditioned exosomes promoted angiogenesis and wound healing in diabetic rats
Diabetic wounds[58]	Exosomes with a bioactive nano-dressing	Adipose stromal cells	The nanodressing-conjugated exosomes significantly enhanced tissue remodeling and re-epithelialization

miRNA: MicroRNA; Nrf2: Nuclear factor E2-related factor 2; lncRNA: Long non-coding RNA; ADSC: Adipose-derived stem cell; MSC: Mesenchymal stem cell.

Table 3 Loaded exosomes in the treatment of diabetic wounds

Pathology	Source of exosome	Modification	Outcome
Diabetic ulcerative wounds[15]	Adipose-derived stem cells	Nrf2	Treatment of animal models with exosomes high in Nrf2 expression significantly reduced ulceration area and promoted angiogenesis
Diabetes-associated impaired wound healing[50]	Adipose-derived mesenchymal stem cells	mmu_circ_0000250	Exosomes modified to contain more mmu_circ_0000250 had a greater effect than unmodified exosomes in endothelial repair in diabetic rats
Diabetes-associated impaired wound healing[84]	Mesenchymal stem cells	ATV	ATV-loaded exosomes enhanced angiogenesis and tissue repair in animal models compared to unmodified exosomes
Diabetic wounds[86]	Mesenchymal stem cells	MiR-155 inhibitor	Loaded exosomes promoted anti-inflammatory action and enhanced re-epithelialization
Diabetic wounds[87]	Adipose stem cells	MiR-21-5P	Loaded exosomes promoted re-epithelialization and angiogenesis. MiR-21-5P was protected from degradation

Studies have shown that exosomes may carry a myriad of therapeutic cargo to end chronic inflammation, enhance wound healing, and promote angiogenesis and re-epithelialization. miRNA: MicroRNA; Nrf2: Nuclear factor E2-related factor 2; ATV: Atorvastatin.