Table 2 Summary of the therapeutic roles of Mφ-EVs in diseases.
Disease models | EVs source and Isolation method | EV subtypes (diameter) | Therapeutic molecules | EV doses and routes | Therapeutic outcomes | References |
|---|---|---|---|---|---|---|
Tissue repair | ||||||
Myocardial I/R injury | - Rat peritonea macrophages - Ultracentrifugation | Exos (~100 nm) | miR-148a | - 2 h before I/R procedure - 2–3 μg per rat by single caudal vein | - Reduced the dysregulation of cardiac enzymes and Ca2+ overload - Reduced apoptosis and the number of broken cardiomyocytes | |
Diabetic skin defects | - RAW 264.7 cell line - Ultracentrifugation | Exos (~95 nm) | Not studied | - The day when wounds were produced - 0.1 or 1 mg EVs in 1 ml PBS per rat by single subcutaneously | - Elevated angiogenesis, migration and proliferation ability of high glucose treated HUVECs by anti-inflammation - Accelerated wound contraction and reduced wound length - Therapeutic effects with dose-dependent | |
Hair loss | - RAW 264.7 cell line - Ultracentrifugation | EVs (~128.8 nm) | Wnt3a/Wnt7b | - 2 days after the hair removed - 0.1 or 1 mg EVs per mouse by intradermally three times weekly for 4 weeks | - Increased proliferation and migration of dermal papilla cells by activating Wnt/β-Catenin pathway - Increased hair follicle number, elongation of hair and thickness of dermis with time- and dose-dependent - Therapeutic effects with dose-dependent | |
Radiation-induced gastrointestinal syndrome | - Mice BMDM - Ultracentrifugation and precipitation | EVs (undefined) | Functional Wnt ligands | Unclear | Elevated survival of mice with wild type BMDM cell medium | |
Inflammatory bowel disease | - Mice BMDM with IL-13/IL-10/IL-1β - Precipitation | Exos (30–150 nm) | CCL1 | - The day when administration with DSS - 50 mg/mouse by intraperitoneally once a day for 8 days | - Reduced length and inflammatory damage of colon - Increased number of Treg cells in spleen - Alleviated weight loss, diarrhea and bleeding in mice with colitis | |
Cutaneous Wound | - Mice BMDM - Ultracentrifugation | Exos (~69 nm) | not specific | - 100 μg/mouse by subcutaneously injection - Once a day at day 1 and 4 | - Increased expression of Arginase and decreased expression of iNOS in M1-like Mφ - Enhanced fibroblast migration and EC tube formation - Increased wound dermal cellularity and collagen production | |
Pathogen control | ||||||
Systemic candidiasis | - THP-1 cell line with Candida albican - Ultracentrifugation | EVs (~30–369 nm) | Proteins | Unclear | - Elevated proinflammatory cytokines by activating ERK2 and p38 - Decreased candidacidal activity | |
Tuberculosis | - THP-1 cell line with mycobacteria - Sucrose gradient centrifugation | Exos (50–100 nm) | Not studied | - 20 μg EVs per mouse by intranasally - Single dose | - Elevated inflammatory response | |
- Mouse BMDM with M.tb - Ultracentrifugation | EVs (undefined) | M.tb-RNA | - 3 weeks after infection - 5 μg/mouse EVs intratracheally at 4 weeks post‐infection | - Decreased replication and survival of M.tb by increased IFN-γ - Elevated autophagy by activating LC-3-associated phagocytosis pathway | ||
- RAW 264.7 cell line with M.tb culture filtrate protein - Ultracentrifugation | Exos (50–150 nm)[112] Exos (30–100 nm)[113] | Immunized purified EVs | - Six weeks before M.tb infection - 40 μg/mouse EVs three times by intranasally at an interval of 2 weeks | - Elevated Th1 response and limited Th2 response - Reduced mycobacterial numbers in lung | ||
Dengue | - U937 Mφ with DENV - Ultracentrifugation | EVs (~100 nm) | NS3 and miRs | Unclear | Elevated production of proinflammatory cytokines in ECs | |
HCV | - Human monocytes-derived Mφ with HIV RNA - Precipitation | Exos (50–100 nm) | miR-29 | Unclear | Decreased HCV replication by inducing the expression of antiviral genes such as IFN-α, ISGs, OAS-1 | |
- THP-1 cell line with IFN - Ultracentrifugation | EVs (50–400 nm) | Not studied | Unclear | Profound inhibition of HCV RNA replication after 72 h or 96 h exposure | ||
Drug delivery | ||||||
Pulmonary metastases | - RAW 264.7 cell line for vitro; mice BMDM for vivo - Precipitation | Exos (~110 nm) | EVs loaded with PTX | - 40 h after i.v. injecting tumor cells - 4 × 1011 particles per mouse by i.v. at the days 1, 4, and 7 | - Higher drug loading and targeting capacity towards cancer cells - Superior antineoplastic efficacy and prolonged lifespan | |
Breast cancer | - RAW 264.7 cell line - Ultracentrifugation | EVs (~110.8 nm) | EVs loaded with DOX or PTX | - Tumor volume reached ~50 mm3 - EVs-PTX (0.5 mg/kg); EVs-DOX (2.5 mg/kg) by i.v. once every 3 days | - Improved loading efficiency of DOX when pH close to PI, of PTX when dissolved in ethanol - Higher affinity towards tumor sites, more robust inhibitory potency on tumor growth and prolonged lifespan of both | |
- RAW 264.7 cell line - Ultracentrifugation | Exos (~97.3 nm) | EVs loaded with DOX | - Tumor volumes reached 60 mm3 - At DOX dose of 5 mg/kg by i.v. every 3 days for total 18 days | - Prolonged circulation time of DOX and better accumulation of DOX at tumor tissue - Highest tumor inhibition efficacy - Decreased other tissue lesions | ||
- J774A.1 cell line - Membrane filter extrusion | EVs (~139 nm) | Hybrid EVs with liposomes and loaded with DOX | Unclear | - Higher drug release in acidic microenvironment - Higher biocompatibility as a safe delivery system with lower cytotoxicity - Decreased K7M2, 4T1, and NIH/3T3 cell viability | ||
Vaccine adjuvant | ||||||
Melanoma | - RAW264.7 cell line with γ-IFN - Ultracentrifugation | Exos (~50 nm) | cytokines such as IL-6, IL-12, and γ-IFN | - Tumor volume reached ~50 mm3 - 10 μg EVs by single subcutaneously at 24 h after injection of vaccine | - Elevated apoptosis of melanoma cancer cells - Decreased celluar scar tissues as well as many infiltrating immune cells - Significant inhibitory effects on tumor growth | |
