Advances in Therapeutic Applications of Extracellular Vesicles

Figures & data

Figure 1 Brief overview of the structure, characteristics and functions of EVs.

Figure 2 Advanced application of EVs. A. Direct therapeutic B. Indirect therapeutic C. Block EVs associated with diseases D. Block the uptake of EVs associated with diseases E. Physical elimination of EVs associated with diseases F. Engineered EVs: drug delivery G. Engineered EVs: Internal modification H. Engineered EVs: parent cell surface modification I. Engineered EVs: EVs surface modification.

Table 1 Examples of Exosomes for Therapeutic Applications

Direct/indirect Therapeutic	Disease	Pathways	Effect	References
MSCs-drived EVs	Retinal ischemia	R28 retinal cells can endocytose MSC-EVs via the HSPG receptor-mediated pathway	Reduce neuroinflammation and promote retinal functional recovery	[81]
ESCs-drived EVs	Stroke	Activate the TGF-β/Smad pathway in CD4 T cells	Induced Treg amplification, regulating neuroinflammation, and promoting nerve recovery	[80]
MSCs-derived exosomes	IVDD	Inhibit ROS production and NLRP3 inflammasome activation	Reduce nucleus pulposus cell apoptosis	[82]
BMSCs-derived exosomes	OA	Downregulated inflammatory cytokines IL-1β, TNF-a, and IL-6 while promoting the expression of the anti-inflammatory cytokines IL-10 and TGF-1.	Reduced synovitis cell infiltration, decreased damage to articular cartilage, and delayed the progression of OA	[83]
BMSCs-derived exosomes	OA	miR-135b in BMSCs-Exo promoted M2 polarization of SMs through targeting MAPK6, thus improving cartilage damage.	Reduce OA-induced upregulation of pro-inflammatory factors in rat’s serum and damage in cartilage tissues	[84]
UMSC-derived exosomes	Phosphorylation	Regulate miR-421 and increase the expression of FOXO3a	Inhibit phosphorylation and release of IL-1β and IL-18, and protecting the process of human parturition	[85]
CDCS-derived EVs	MI	Enhancing cardiomyocyte viability and preventing oxidative stress.	Improve cardiac function	[86]
Block EVs Associated with Diseases	Disease	Pathways	Effect	References
Calcitonin	PC	Inhibits EV release and causes the accumulation of docetaxel and methotrexate within tumor cells	Significant reduction in tumor cell proliferation	[89]
Manumycin A	PC and HCC	Inhibit Ras enzyme, ESCRT, and hnRNP H1	Inhibit EVs associated with diseases secretion	[91–93]
Pantethine	PbA	Affects the membrane lipid bilayer recombination process in MV formation by reducing lipid metabolism and total cholesterol levels	Prevent the occurrence of cerebral malaria	[96]
GW4869	Melanoma	Affects lipid metabolism, and can be used as a non-competitive inhibitor of membrane lipid nSMase to indirectly inhibit exosome release.	Inhibit the autosecretory regulatory proliferation of mouse B16BL6 cells	[97]
Block the Uptake of EVs Associated with Diseases	Disease	Pathways	Effect	References
Heparin and protease K	OC, GBM and melanoma	Reduce exosome uptake and internalization by cancer cells.	Inhibit tumor invasion	[106–108]
Knock down dynamin2 or overexpress a dominant-negative form of dynamin2	Leukemia	Exosome uptake is related to clathrin and cavin endocytosis pathways	Inhibit tumor invasion	[104]
Physical Elimination of EVs Associated with Diseases	Disease	Pathways	Effect	References
Physical elimination	BC	Target cancer cell exosomes by specifically targeting the HER2 on their surface	Block communication between cancer cells and inhibit cancer cell invasion	[111,112]

Abbreviations: MSCs, mesenchymal stem cells; EVs, extracellular vesicles; HSPG, heparin sulfate proteoglycans; ESCs, embryonic stem cells; Treg, regulatory T cells; IVDD, intervertebral disc degeneration; ROS, reactive oxygen species; BMSCs, bone marrow stem cells; OA, osteoarthritis; M2, macrophages 2; UMSCs, umbilical cord mesenchymal stem cells; CDCs, cardiosphere derived cells; MI, myocardial infarction; PC, prostate cancer; HCC, hepatocellular carcinoma; ESCRT, endosomal sorting complex required for transport; hnRNP H1, heterogeneous nuclear ribonucleoprotein H1; PbA, Plasmodium berghei strain ANKA; nSMase, neutral sphingomyelinase; OC, ovarian cancer; GBM, glioblastoma multiforme; BC, breast carcinoma; HER2, human epidermal growth factor receptor 2.

Table 2 Examples of Exosomal Contents for Clinical Diagnostic Applications

Protein(s)	Disease	Body Fluid	Correlation	References
ApoA1	PD	Blood serum	Up-occurrence	[119]
HSP90	ALS	Blood plasma	Up-occurrence	[121]
LGALS3BP	EC	Blood plasma	Up-occurrence	[122]
miRNA(s)	Disease	Body Fluid	Correlation	References
miR-425, miR-744, and miR-92b-5p	HF	Blood serum	miR-425, miR-744, miR-92b-5p-up-occurrence	[123,125]
miR-21-3p, miR-132, and miR-200	MH	Blood serum	Up-occurrence	[128,130]
miR-24, miR-106a	AAA	Blood serum	miR-106a-up-occurrence, miR-24-up-remission	[131,132]
miR-122-5p, miR-17-5p, miR-126-5p, and miR-145-3p	AMI	Blood serum	Up-occurrence	[133,134]
miR-21-5p	Low-AFP HCC	Blood plasma	Up-occurrence	[135]
miR-145, miR-155, miR-382, and miR-148a	BC	Blood serum	miR-145, miR-155, miR-382-up-occurrence, miR-148a-down--occurrence	[136,137]
miR-21-5p	Acromegaly	Blood serum	Up-occurrence	[139]
CircRNA(s)	Disease	Body Fluid	Correlation	References
Circ_0051443	HCC	Blood plasma	Down-occurrence	[143]
Circ_NRIP1	GC	Blood plasma	Up-occurrence	[144]
Circ_GAPVD1	CRC	Blood plasma	Up-occurrence	[145]
lncRNA(s)	Disease	Body fluid	Correlation	References
lncRNA-DLX6-AS1 and lncRNA-PRINS	DR	Blood plasma	Up-occurrence	[147]
lncRNA-LOC107986997	AF	Blood serum	Up-occurrence	[148]
lncRNA-Linc00662, lncRNA -CHASERR and lncRNA-PCA3	PC	Urine	Up-occurrence	[149]
tRNA(s)	Disease	Body Fluid	Correlation	References
tRNA-ValTAC-3, tRNA-GlyTCC-5, tRNA-ValAAC-5, and tRNA-GluCTC-5	HCC	Blood plasma	Up-occurrence	[150]
tRF-Leu-TAA-005, tRF-Asn-GTT-010, tRF-Ala-AGC-036, tRF-Lys-CTT-049, and tRF-Trp-CCA-057	NSCLC	Blood plasma	Down-occurrence	[151]
tRF3-Ile-AAT-1 and tiRNA5-Lys-CTT-1	LN	Urine	Up-occurrence	[152]

Abbreviations: miRNA, microRNA; CircRNAs, circular RNAs; lncRNAs, long noncoding RNAs; tRNAs, transfer RNAs; ApoA1, apolipoprotein A1; PD, parkinson’s disease; HSP90, heat shock protein 90; ALS, amyotrophic lateral sclerosis; LGALS3BP, lectin galactoside-binding soluble 3 binding protein; EC, endometrial cancer; HF, heart failure; MH, myocardial hypertrophy; AAA, abdominal aortic aneurysm; AMI, acute myocardial infarction; Low-AFP HCC, low-alpha fetoprotein hepatocellular carcinoma; BC, breast cancer; GC, gastric carcinoma; CRC, colorectal cancer; DR, diabetic retinopathy; AF, atrial fibrillation; PC, prostate cancer; NSCLC, non-small cell lung cancer; LN, lupus nephritis.

Table 3 Engineered Exosome-Based Drug Delivery Systems

Engineer Method (Drug Delivery)	Disease	Exosome Source	Character	References
Erastin‐loaded exosomes labeled with FA to target TNBC cells with overexpression of FA receptors	TNBC	HFL-1	Actively and selectively target MDA-MB-231 cells and efficiently induce ferroptosis in tumor cells	[161]
Exosomes loaded with DOX	TNBC	Macrophage cell	Avoids the disadvantages of easy clearance and high toxicity in vivo and targets tumor cells more precisely	[162]
Exosomes loaded with BDNF	Ischemic stroke	HNSC	BDNF-hNSC-Exo resulted in reduced infarct volume and improved neurological function	[163]
Exosomes have been bioengineered to carry the inhibitor of NF-κB	Premature birth	HEK293T cells	Slow the migration of fetal immune cells and delayed preterm birth	[164]
Engineer Method (EVs Internal Modification)	Disease	Exosome Source	Character	References
HNSCC is associated with regulation of miRNA transfection into Evs	HNSCC	WSU-HN6 cells	Transfection of different miRNAs regulates the promotion and promotion of tumor growth	[170]
DOX successfully loaded into exosomes by electroporation	TUBO breast cancer cell line	Mesenchymal stem cells	The type of exosome reduced the tumor growth rate compared to free DOX and non-targeted DOX loaded exosomes	[173]
The exosomes were loaded with a batch of fluorescently labeled miR-26a by electroporation	LC	Human 293T cells	Engineered exosomes containing miR-2a are effectively endocytosed by HepG2 cells. Subsequently, up-regulated miR-2a in HepG2 cytoplasm inhibits the migration and proliferation rate of cancer cells	[174]
Engineered M(Parent Cell Surface Modification)	Disease	Exosome Source	Character	References
The CAR is loaded onto the surface of the T cell	BC	CAR-T cells	Exosomes expressed by CAR T cells showed a good antitumor effect, and the exosomes containing CAR did not express PD-1 protein to avoid the influence of PD-L1 on tumor cell membrane	[178]
Engineered Method (EVs Surface Modification)	Disease	Exosome Source	Character	References
EVs secreted by adipose-derived mesenchymal stem cells can rebind with FPG3 to form exo@FPG3	Vascular injury	ADSC	Achieve HUVECs specific targeting	[181]
Her2-targeting peptides were fused to the N terminus of LAMP2 on the exosome surface and fused with green fluorescent GFP	RC	THLG-293T or LG-293T cells	More accurate delivery of 5-FU and miR-21i to CRC cell HCT-116 to achieve the purpose of treating CRC and tracking drug uptake and metabolism	[184]
Antibodies to T cell membrane surface protein CD3 and EGFR antibodies to breast cancer cell membrane protein were added to exosomess	BC	Expi293F cell	SMART-Exos can specifically enhance the immune response of T cells to BC cells and inhibit tumor growth	[185]
IOPN are loaded onto the exosome surface	AIS	SMCs	Exosomes can navigate to the target area under the guidance of the external magnetic field, which increases the concentration of the location by 5.1 times	[186]
Exosomes surface loaded with ASO targeting STAT6 transcription factors	TAMs	HEK	TAMs were reprogrammed into a proinflammatory M1 phenotype to play an anti-tumor role	[187]
EVs surfaces were loaded with polyethylene glycol, expressed with CD47, or combined with albumin binding domains	The clearance rate of EVs in vivo is higher	HEK-293T, N2A, or CDCs	Prolong its circulation time in the body	[190,192,193]

Abbreviations: FA, folate; TNBC, triple negative breast cancer; HFL-1, human lung fibroblasts-1; DOX, doxorubicin; BDNF, brain-derived neurotrophic factor; HNSCs, human neural stem cells; BBB, blood-brain barrier; NF-κB, nuclear factor kappa-B; HNSCC, head and neck squamous cell carcinoma; LC, liver cancer; CAR, chimeric antigen receptor; PD-1, programmed death-1; PD-L1, programmed cell death 1 ligand 1; BC, breast cancer; FPG3, fluorinated peptide dendrimers; ADSC, adipose-derived mesenchymal stem cells; HUVECs, human umbilical vein endothelial cells; GFP, green fluorescence protein; RC, rectal cancer; 5-FU, 5-fluorouracil; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; IOPN, iron oxide nanoparticles; AIS, acute ischemic stroke; ASO, antisense oligonucleotides; STAT6, signal transducer and activator of transcription 6; TAMs, tumor-associated macrophages; HEK, human embryonic kidney; M1, macrophage1; CD, cluster of differentiation; N2A, Neuro2A; CDCs, cardiosphere-derived cells.

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