Multifunctional Milk-Derived Small Extracellular Vesicles and Their Biomedical Applications
Abstract
:1. Introduction
2. Biogenesis and Characteristics of sEVs
3. Isolation and Purification of msEVs
3.1. Common Methods for sEV Purification
3.2. Large-Scale Purification of High-Purity msEVs
4. Composition and Functions of msEVs
4.1. Composition of msEVs
4.1.1. Proteins
4.1.2. Nucleic Acids
4.1.3. Polysaccharides and Oligosaccharides
4.1.4. Lipids
4.2. Function of msEVs
4.2.1. Immunoregulation
4.2.2. Regulation of Intestinal Tract Function
4.2.3. Regulation of Muscle and Bone Development
4.2.4. Promote Skin Regeneration
4.2.5. Detection of Bovine Diseases
4.2.6. Other Functions
4.3. Potential Health Risks Associated with msEVs
5. MsEVs as Drug Delivery Vehicles
5.1. Biosafety of msEVs
5.2. Engineering of msEVs
5.2.1. Cargo Loading
5.2.2. Modification of msEVs
5.3. MsEVs for Drug Delivery
5.3.1. Delivery of Chemical Drugs
5.3.2. Delivery of Nucleic Acids
5.3.3. Delivery of Other Small Molecules
6. MsEVs and Nutritional Supplements
7. Conclusions and Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BLV | Bovine leukemia virus |
BTN | Butyrophilin |
DAI | Disease activity index |
DNMT1 | DNA methyltransferase 1 |
DSS | Dextran sulfate sodium salt |
DOX | Delivering doxorubicin |
DOX | Delivering doxorubicin |
DSPE | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine |
DP | Dermal papillary cell |
DHT | Dihydrotestosterone |
ECG | Epigallocatechin gallate |
ENP | Exosome nanopuncturer |
ESCRT | Endosomal sorting complex required for transport |
FA | Folic acid |
HA | Hyaluronic acid |
LNPs | Lipid nanoparticles |
lncRNA | Long non-coding RNA |
LPS | Lipopolysaccharide |
msEVs | Milk-derived small extracellular vesicles |
miRNA | MicroRNA |
mRNA | Messenger RNA |
ncRNA | Non-coding RNA |
NEC | Necrotizing enterocolitis |
PAC | Paclitaxel |
PEG | Polyethylene glycol |
sEVs | Small extracellular vesicles |
SEC | Size-exclusion chromatography |
siRNA | Interfering RNA |
SAM | Severe acute malnutrition |
TFF | Tangential flow filtration |
TLR4 | Toll-like receptor 4 |
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sEVs Proteins | MW (kDa) | Classification | Function | Specimen Source |
---|---|---|---|---|
CD63 | 63 | Four transmembrane proteins | It is a lysosomal membrane protein with the activity of activating platelet surface antigens; | Bovine milk [34,36,37], mesenchymal stromal cells [38], and plasma [39,40]; |
CD9 | 24–27 | Four transmembrane proteins | Participate in the interaction between cells and the outside world; | Bovine milk [36], mesenchymal stem cells [41,42], and saliva [43,44]; |
CD81 | 81 | Four transmembrane proteins | Key structural sites for perceiving external signals in cells; | Bovine milk [37,45], synovial fluid [46], and cerebrospinal fluid [47]; |
TSG101 | 44 | Internal signature proteins | A component of the functional ESCRT-I complex that regulates vesicular transport; | Bovine milk [34,48], rat serum [40], and bile [49]; |
ALIX | 95 | Internal signature proteins | A phylogenetically conserved cytosolic scaffold protein; | Bovine milk [34,36,48], brain [50], and fibroblast [51]; |
HSP70 | 70 | Internal signature proteins | It is an important member of the heat shock protein family. | Bovine milk [34,45], plasma [39,44], and urine [52,53]. |
Separation Method | Principle | Purity | Production | Time Consuming | References |
---|---|---|---|---|---|
PEG precipitation purification | Macromolecule aggregation precipitation; | + | +++ | + | [57] |
Ultracentrifugation | Difference of sedimentation coefficient; | ++ | ++ | ++ | [53,58,59] |
Density gradient centrifugation | Density gradient difference; | +++ | + | +++ | [60] |
Ultrafiltration centrifugation | Specific molecular weight cutoff; | ++ | +++ | + | [61] |
Tangential Flow Filtration | Tangential filtering; | ++ | +++ | + | [62] |
Size exclusion chromatography | Particle size difference; | +++ | ++ | ++ | [63,64,65] |
Affinity purification | Intermolecular specific binding. | ++++ | + | ++ | [66] |
Function | Therapeutic Agent | Effect | Mechanism | References |
---|---|---|---|---|
Immunoregulation | TGF-β and miRNA-30b | Play a crucial role in the biogenesis and improvement of infant immune function. | Regulation of immune-related factors (such as miRNAs and antibodies). | [100,101,102,103,104,105,106] |
Regulation of intestinal tract function | bta-miR-34a, miR-155, and miR-146a | Antioxidant stress; Resistance to hypoxic injury; Reduce the inflammatory response induced by LPS, DSS, and other factors in the mouse intestinal model. | Enhance cell activity, inhibit inflammation, regulate intestinal flora, etc. | [107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123] |
Development of muscle and bone | miR-21 and miR-29a | The growth and development of muscle and bone can be altered by miRNAs from msEVs. | Increase the number of osteoblasts, promote bone formation and osteoblast differentiation, and encourage myofiber formation in myotube cells. | [124,125,126,127] |
Promote skin regeneration | TGF-β and miRNA-21 | Promote the transformation of inflammation into tissue and further promote the healing of skin wounds. | Induce ECM deposition and regulate tissue regeneration by regulating the phosphorylation of the Smad pathway. | [128] |
Detection of bovine diseases | Bovines can be monitored for infection with pathogenic bacteria such as Staphylococcus aureus or their health status. | Examining the nucleic acids, proteins, and lipids in msEVs to identify illness signs. | [129,130,131,132,133,134] | |
Alleviates arthritis symptoms | immunoregulatory microRNAs (miR-30a, miR-223, miR-92a), beta-lactoglobulin mRNA, and milk-specific beta-casein | Delayed the onset of arthritis, and histology showed diminished cartilage pathology and bone marrow inflammation in both models. | Decreased MCP-1 and IL-6 production by splenic cells in serum; Decreased splenic Th1 (Tbet) and Th17 (RORT) mRNA levels, which were also associated with decreased anticollagen IgG2a levels. | [135] |
Reduce the side effects of chemotherapy | Protect cells from chemotherapeutic drug-induced cytotoxicity. | Affect the cell cycle of RAW 264.7 with and without cisplatin. | [136] | |
Use in MOG-specific immunotherapy | butyrophilin (BTN) | Could be thought of as an attractive method to help patients with multiple sclerosis develop MOG-specific tolerance. | The BTN content of these vesicles can pass past the skin’s epidermis and other biological barriers, serving as Trojan horses for the body. | [137] |
Can be a useful medicinal ingredient for improving skin lightening | miR-2478 | Inhibit melanin production. | Through the Akt-GSK3 signaling pathway, Rap1a expression inhibition reduced melanogenesis. | [138] |
Might become a potential way to treat cardiac fibrosis | Improved heart performance in cardiac fibrosis rats. | Significant improvements were made to the proangiogenic growth factors. | [139] | |
Have the potential to promote hair regeneration. | Promote hair regeneration. | Promote dermal papillary cell (DP) proliferation and rescue dihydrotestosterone (DHT)-induced follicular development arrest. | [140] |
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Zhong, Y.; Wang, X.; Zhao, X.; Shen, J.; Wu, X.; Gao, P.; Yang, P.; Chen, J.; An, W. Multifunctional Milk-Derived Small Extracellular Vesicles and Their Biomedical Applications. Pharmaceutics 2023, 15, 1418. https://doi.org/10.3390/pharmaceutics15051418
Zhong Y, Wang X, Zhao X, Shen J, Wu X, Gao P, Yang P, Chen J, An W. Multifunctional Milk-Derived Small Extracellular Vesicles and Their Biomedical Applications. Pharmaceutics. 2023; 15(5):1418. https://doi.org/10.3390/pharmaceutics15051418
Chicago/Turabian StyleZhong, Youxiu, Xudong Wang, Xian Zhao, Jiuheng Shen, Xue Wu, Peifen Gao, Peng Yang, Junge Chen, and Wenlin An. 2023. "Multifunctional Milk-Derived Small Extracellular Vesicles and Their Biomedical Applications" Pharmaceutics 15, no. 5: 1418. https://doi.org/10.3390/pharmaceutics15051418