Blood cell-derived extracellular vesicles: diagnostic biomarkers and smart delivery systems

Figures & data

Table 1. Significance of blood-derived EV-related molecules in diseases

EV type	Related molecules	Functional change	Possible mechanism	Disease	Ref.
REVs	α-syn	elevated	excess oligomeric a-syn interacts with EAAT2 to inhibit glutamate uptake by astrocytes	Parkinson’s disease	19
LEVs	miR-146a, miR-128, miR-185, miR-365, and miR-503	elevated	these miRNAs decrease cell migration and promote macrophage entrapment in the vessel wall	atherosclerosis	43
PEVs	serotonin	elevated	platelet-derived serotonin promotes the transit of PEVs to lymph nodes, activates autoantibodies, and increases vascular permeability	rheumatoid arthritis	57
plasma EVs	transforming growth factor-beta 1 (TGF-β1)	elevated	TGF-β1 significantly inhibits NK cell activity in cytotoxicity assays	relapsed leukemia	67
plasma EVs	miR-212 and miR-132	decreased	these miRNAs lose their protective effect on neurons	Alzheimer’s disease	68
plasma EVs	α-syn	elevated	α-syn activates microglia and astroglia, enhancing neurodegeneration	Parkinson’s disease	69

Figure 1. The function of erythrocyte-derived extracellular vesicles (REVs) REVs elicit immune-inflammatory responses by modulating the biological activities of both T cells and B cells. REVs stimulate monocytes to produce proinflammatory cytokines and chemokines, which promote T cell proliferation and further stimulate T cells to produce TNF, IL-6, and IL-8. REVs also inhibit the expression of Blimp-1 and IRF4 and activation of the NF-κB pathway, which inhibit B cell function. Additionally, REVs mediate blood coagulation by activating coagulation factors such as FXI, which initiates and promotes thrombin production

Table 2. Summary of blood cell-derived EVs for drug delivery

EV source	Cargo	Loading method	Disease	Ref.
erythrocytes	antisense oligonucleotides	electroporation	breast cancer	28
erythrocytes	atovaquone and tafenoquine	coincubation	P. falciparum	29
platelets	TPCA-1	coincubation	pneumonia	59
plasma	miR-31 and miR-451a	electroporation	liver cancer	75

TPCA-1, [5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide

Figure 2. Characterization of erythrocyte-derived extracellular vesicles (REVs)

The typical morphology of REVs was characterized using TEM and NTA. The biomarkers of REVs were detected using Western blotting.(A) Size distribution of REVs analyzed using NTA.(B) Western blot analysis of CANX, ALIX, HSP-70, CD63, Flotillin, TSG101, and hemoglobin in erythrocyte lysates and REVs.(C) TEM images of REVs. Scale bar, 200 nm.

Figure 3. The function of leukocyte-derived extracellular vesicles (LEVs)

LEVs are involved in coagulation and immune-inflammatory responses. These vesicles promote activation of the coagulation pathway via TF.T cell-derived EVs also positively regulate DC function, and B cell-derived extracellular vesicles impair the T cell response. Cell surface proteins (selectin, integrin, and complement regulators) on neutrophil-derived extracellular vesicles mediate the specific adherence of these extracellular vesicles to monocytes and endothelial cells. Therefore, LEVs induce inflammation-stimulating cellular signaling pathways. In addition, LEVs can increase TGF-β1 release from MDMs, which blocks the response of MDMs to LPS and zymosan.

Figure 4. The function of platelet-derived extracellular vesicles (PEVs)

PEVs are involved in various biological processes, such as coagulation, immune-inflammatory responses, and tumorigenesis. PEVs can enhance platelet aggregation and thrombin formation. Additionally, PEVs also inhibit IL-17 and IFN-γ production by T cells via P-selectin and CXCR3 while stimulating the monocyte inflammatory response through P-selectin-dependent adhesion. In addition, PEVs also promote IgG secretion by delivering CD154 to B cells. During tumor progression, PEVs can increase tumor angiogenesis by increasing the content of miR-126, EGF, and PDGF-α. These vesicles directly promote tumor cell proliferation, invasion, and metastasis via elevated levels of miRNA-939, miRNA-223, and MMP-2.

Figure 5. Erythrocyte-derived extracellular vesicles (REVs) for therapeutic delivery To optimize the targeted delivery of REVs, chemical modifications introduced by approaches such as click chemistry and lipidation can anchor the targeted motifs, including proteins, aptamers, peptides, and antibodies, on the exosomal membrane. Additionally, REVs can be modified using the CP05 peptide, with affinity for CD63, to introduce an exogenous target motif for display on the exosomal membrane

Data Availability Statement

All data generated in the current study were included in this article.