Bioengineered Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles as an Improved Drug Delivery System: Methods and Applications
Abstract
:1. Introduction
2. Fundamentals of EVs: Biogenesis, Composition and Uptake
3. Strategies to Maximize the Therapeutic Efficacy of EVs
3.1. Cargo Customization
3.1.1. Exogenous Cargo Loading
3.1.2. Endogenous Cargo Loading
3.2. Surface Functionalization
3.2.1. Genetic Manipulation of Parental Cells
3.2.2. Chemical Modification
3.2.3. Hybrid Membrane Engineering
4. Current Applications of MSC-EVs
4.1. Loading MSC-EVs with Therapeutic Cargo
Type of Strategy | Cargo | Application | Therapeutic Effect | MSC Source | Ref. |
---|---|---|---|---|---|
Nucleic Acids | |||||
Endogenous loading (transduction) | miR-122 | Liver fibrosis | Inhibited fibrosis | Human/mouse AT | [93] |
miR-124a | Glioblastoma | Increased survival of GSC-injected mice | Human BM | [89] | |
miR-126 | Skin wounds | Increased re-epithelialization, angiogenesis, and collagen maturity | Human SM | [94] | |
miR-17-92 | Ischemic stroke | Enhanced axon-myelin remodelling and functional recovery after stroke | Rat BM | [95] | |
miR-379 | Breast cancer | Inhibited tumour growth | Human BM | [90] | |
miR-let7c | Renal fibrosis | Decreased fibrosis | Human BM | [96] | |
mRNA-CD-UPRT | Cancer | Inhibited tumour growth | Human AT, BM, DP and WJ | [97] | |
Endogenous loading (transfection) | miR-126 | Ischemic stroke | Increased neurogenesis and improved functional recovery after stroke | Rat AT | [98] |
miR-133b | Spinal cord injury | Inhibited inflammatory response and induced nerve function repair | Rat BM | [99] | |
miR-150-5p | Rheumatoid arthritis | Inhibited synoviocyte hyperplasia and angiogenesis | Mouse BM | [100] | |
miR-155-5p | Osteoarthritis | Increased proliferation and migration, suppressed apoptosis and enhanced ECM secretion of osteoarthritic chondrocytes | Human SM | [101] | |
miR-16-5p | Colorectal cancer | Inhibited tumour growth | Human BM | [91] | |
miR-181c | Burn-induced inflammation | Decreased inflammation | Human WJ | [102] | |
miR-22 | Spinal cord injury | Inhibited inflammatory response and induced nerve function repair | Rat BM | [103] | |
miR-26a | Spinal cord injury | Promoted axonal regeneration and neurogenesis | Rat BM | [104] | |
miR-29b | Alzheimer’s disease | Reduced the pathological effects of amyloid-β peptides | Rat BM | [105] | |
miR-424 | Ovarian cancer | Inhibited tumorigenesis and angiogenesis | Human BM | [92] | |
miR-92a-3p | Osteoarthritis | Enhanced cartilage development and homeostasis | Human BM | [106] | |
Exogenous loading (electroporation) | miR-124 | Ischemic stroke | Increased neurogenesis | Mouse BM | [107] |
miR-132 | Myocardial infarction | Enhanced neovascularization and preserved heart functions | Mouse BM | [108] | |
miR-499a-5p | Endometrial cancer | Inhibited tumour growth and metastasis | Mouse BM | [109] | |
miR-590-3p | Myocardial infarction | Promoted cardiomyocyte proliferation and cardiac regeneration | Rat BM | [110] | |
siR-CTGF | Spinal cord injury | Increased axon regeneration and motor function after SCI | Rat BM | [111] | |
siR-galectin-9 | Pancreatic ductal adenocarcinoma | Inhibited tumour growth | Human BM | [112] | |
siR-Kras | Pancreatic ductal adenocarcinoma | Inhibited tumour growth | Human BM | [113] | |
siR-PLK-1 | Bladder cancer | Increased cytotoxicity and apoptosis | Human BM | [114] | |
si-SHN3 | Osteoporosis | Enhanced osteogenic differentiation and vessel formation and inhibited osteoclast formation | iPSC | [115] | |
Exogenous loading (incubation) | cholesterol-modified miR-210 | Ischemic stroke | Increased angiogenesis and survival of ischemic brain mice | Mouse BM | [116] |
siR-PTEN | Spinal cord injury | Increased functional recovery of spinal cord lesion in rats | Human BM | [117] | |
Exogenous loading (transfection reagent) | miR-326 | Inflammatory bowel disease | Inhibited the synthesis and production of inflammatory factors | Human WJ | [118] |
Proteins | |||||
Endogenous loading (protein transduction) | Akt | Myocardial infarction | Increased angiogenesis and cardiac regeneration | Human WJ | [119] |
Ang-2 | Skin wounds | Increased angiogenesis and accelerated wound healing | Human WJ | [120] | |
Osteoactivin | Osteoporosis | Increased proliferation and osteogenesis of MSC and attenuated bone loss in ovariectomized rat | Rat BM | [121] | |
PEDF | Ischemic stroke | Ameliorated cerebral ischemia–reperfusion injury in rats | Rat AT | [122] | |
Small molecules | |||||
Endogenous loading (incubation) | Iron oxide NPs | Skin wounds | Improved targeting under an external magnetic field and enhanced wound healing | Human WJ | [123] |
PTX | Pancreatic adenocarcinoma | Decreased tumour growth | Mouse BM | [62] | |
TXL | Metastatic breast cancer; ovarian cancer; lung carcinoma | Inhibited tumour growth | Human WJ | [124] | |
Venofer | Cancer | Increased tumour cell death under an external magnetic field | Human AT, BM, DP and WJ | [125] | |
Exogenous loading (dialysis) | DOX | Osteosarcoma | Inhibited tumour growth | Mouse BM | [126] |
Exogenous loading (electroporation) | DOX | Colon adenocarcinoma | Inhibited tumour growth | Mouse BM | [127] |
NCTD | Hepatocellular carcinoma | Inhibited tumour growth | Human BM | [128] | |
Exogenous loading (electroporation/sonication) | GEMP/PTX | Pancreatic ductal adenocarcinoma | Increased homing and penetration, and anti-tumour potency | Human BM | [129] |
Exogenous loading (extrusion) | PTX | Breast cancer | Decreased tumour growth | Human BM | [130] |
Exogenous loading (freeze–thaw) | polypyrrole NPs | Diabetic peripheral neuropathy | Reduced the neural and muscular damage under electric stimulation | Rat BM | [131] |
Exogenous loading (incubation) | Cur | Ischemic stroke | Decreased inflammation | Mouse BM | [132] |
Exogenous loading (incubation; sonication) | TKI | Anaplastic thyroid cancer | Increased radioiodine sensitivity | Human AT | [133] |
4.2. Improving the Therapeutic Potential of MSC-EVs via Surface Engineering
5. Clinical Translation of Bioengineered MSC-EVs
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Type of Strategy | Surface Modification | Application | Therapeutic Effect | MSC Source | Ref. |
---|---|---|---|---|---|
Genetic surface engineering | cTnI-targeting peptide | Myocardial infarction | Improved targeting to ischemic heart | Rat BM | [110] |
HER2-specific DARPins | Breast cancer | Improved uptake by HER2-positive cells | N/A | [134] | |
IL-2 | Cancer | Activated human CD8+ T-killers | Human AT | [135] | |
IL-6ST decoy receptors | Duchenne muscular dystrophy | Counteracted the effects of pathological signalling pathways | Human BM | [136] | |
CSTSMLKAC peptide | Myocardial infarction | Improved targeting to ischemic heart | Mouse BM | [137] | |
PD-L1 | Autoimmune Diseases | Improved recognition and inactivation of immune cells | Mouse BM | [138] | |
RVG | Ischemic stroke | Increased targeting to ischemic brain | Mouse BM | [107] | |
TNF-α | Cancer | Inhibited tumour growth | Human N/A | [139] | |
TRAIL | Cancer | Increased selective apoptosis | Human N/A | [140] | |
Chemical surface engineering | 5TR1 DNA aptamer | Colon adenocarcinoma | Improved targeting to tumours | Mouse BM | [127] |
BM-specific RNA aptamer | Osteoporosis | Improved targeting to bone marrow | Mouse BM | [141] | |
c(RDGyK) peptide | Ischemic stroke | Improved targeting to ischemic brain | Mouse BM | [116,132] | |
IL-4R-targeting peptide | Anaplastic thyroid cancer | Improved targeting to tumours | Human BM | [142] | |
LJM-3064 aptamer | Multiple sclerosis | Increased affinity to myelin-producing cells; induced immunomodulatory and remyelination effects | Mouse BM | [143] | |
OXA | Pancreatic ductal adenocarcinoma | Induced immunogenic tumour cell death | Human BM | [112] | |
RVG | Alzheimer’s disease | Improved targeting to brain tissues | Mouse BM | [144] | |
SDSSD peptide | Osteoporosis | Improved targeting to osteoblasts and bone-forming surfaces | iPSC | [115] | |
SPION | Melanoma subcutaneous cancer | Improved targeting under an external magnetic field | Human N/A | [139] | |
εPL-PEG-DSPE | Osteoarthritis | Increased uptake and retention in cartilage | iPSC | [145] | |
Macrophage membranes fractions | Spinal cord injury | Increased levels of ischemic region-targeting molecules and improved targeting to injury | Human WJ | [146] | |
Hybrid membrane engineering | Monocyte membranes fractions | Myocardial infarction | Improved targeting to ischemic myocardium | Rat BM | [147] |
PEGylated liposomes | Cancer | Decreased internalization by macrophages | Mouse BM | [84] | |
Platelet membrane fractions | Myocardial infarction | Improved targeting to injured myocardium and enhanced cellular uptake by endothelial cells and cardiomyocytes | Human BM | [148] |
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Ulpiano, C.; da Silva, C.L.; Monteiro, G.A. Bioengineered Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles as an Improved Drug Delivery System: Methods and Applications. Biomedicines 2023, 11, 1231. https://doi.org/10.3390/biomedicines11041231
Ulpiano C, da Silva CL, Monteiro GA. Bioengineered Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles as an Improved Drug Delivery System: Methods and Applications. Biomedicines. 2023; 11(4):1231. https://doi.org/10.3390/biomedicines11041231
Chicago/Turabian StyleUlpiano, Cristiana, Cláudia L. da Silva, and Gabriel A. Monteiro. 2023. "Bioengineered Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles as an Improved Drug Delivery System: Methods and Applications" Biomedicines 11, no. 4: 1231. https://doi.org/10.3390/biomedicines11041231