The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy

Qian, Kewen; Fu, Wenyan; Li, Tian; Zhao, Jian; Lei, Changhai; Hu, Shi

doi:10.1186/s13046-022-02492-1

Journal of Experimental & Clinical Cancer Research

Table 1 sEVs as cargo carriers for cancer therapy

From: The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy

Therapeutic method	Therapeutic cargo	Targeting strategy	Therapeutic mechanism	Function	Cancer type	Particle Size	Purification and enrichment	Origin	Reference
chemotherapy	thymidine kinase (TK)/nitroreductase (NTR)	____	TK-NTR mediated conversion of prodrugs ganciclovir and CB1954 into cytotoxic agents	tumor killing	breast cancer	MVs mean 140 nm and exosomes mean 115 nm	ultracentrifugation	4T1, MDA-MB-231, BT474, MCF-7 cells	[184]
	cytosine deaminase (CD)/uracil phosphoribosyltransferase (UPRT)	____	CD-UPRT mediated conversion of prodrug 5-FC into 5-FU	inhibit tumor growth	schwannoma	MVs mostly 100–150 nm	ultracentrifugation and sucrose gradient ultracentrifugation	HEK 293 T cells	[185]
	cytosine deaminase (CD)/uracil phosphoribosyltransferase (UPRT)	____	CD-UPRT mediated conversion of prodrug 5-FC into 5-FU	inhibit tumor growth	glioblastoma	EVs mostly 80-150 nm	ultracentrifugation	HEK 293 T cells	[186]
	palladium (Pd) catalysts	cancer cell-derived naïve tropism	Pd-mediated dealkylation of prodrug panobinostat	inhibit tumor growth	non-small cell lung carcinoma (NSCLC)	Exosomes 100-140 nm	ultracentrifugation	A549 cells and glioma U87 cells	[187]
	doxorubicin (Dox)	monocyte or macrophage-derived naïve tropism	enhanced tumor tropism as sEVs derived from monocytes and macrophages	anti-angiogenesis inhibit tumor growth with reduced systemic cytotoxicity	colorectal cancer	Exosomes 120–130 nm	ultracentrifugation and sucrose gradient ultracentrifugation	U937 cells and Raw 264.7 cells	[188]
	paclitaxel (PTX)	mesenchymal stromal cell (MSC)-derived naïve tropism	enhanced tumor tropism as sEVs derived from MSCs	inhibit tumor growth with reduced systemic cytotoxicity	pancreatic cancer	MVs mostly below 100 nm	ultracentrifugation	SR4987 cells	[189]
	doxorubicin (Dox)	αv integrin-specific iRGD peptide	iRGD peptide-mediated target to tumor site and Dox	inhibit tumor growth with reduced systemic cytotoxicity	breast cancer	Exosomes mean 97 nm	ultracentrifugation	immature mouse dendritic cells	[190]
	doxorubicin (Dox)	a peptide targeting the mesenchymal-epithelial transition factor (c-Met)	c-Met-specific peptide-mediated target to tumor site and Dox	inhibit tumor growth	triple-negative breast cancer (TNBC)	Exosomes mean 97.3 nm	ultracentrifugation	macrophages	[191]
	paclitaxel (PTX)	c(RGDyK) peptide	c(RGDyK) peptide-mediated target to tumor site and PTX	inhibit tumor growth with reduced systemic cytotoxicity	glioblastoma	Exosomes 70.2 ± 18 nm	ultracentrifugation	embryonic stem cells	[192]
	paclitaxel (PTX)	sigma-specific aminoethylanisamide (AA)	AA-mediated target to tumor site and PTX	inhibit tumor growth suppress pulmonary metastasis	lung cancer	Exosomes 110.8 ± 4.1 nm by NTA and 75.9 ± 2.6 nm by DLS	size exclusion chromatography	Raw 264.7 cells and primary bone marrow-derived macropahges	[193]
	paclitaxel (PTX)	diacyllipid–aptamer sgc8	sgc8-mediated cellular uptake through multiple endocytosis pathways	induce endocytosis of tumor cells	human T leukemia cell	mean 111.4 nm	ultracentrifugation	immature mouse dendritic cells	[194]
	paclitaxel (PTX)	nucleolin-targeting aptamer AS1411	AS1411-mediated target to tumor site and PTX	inhibit tumor growth	breast cancer	Exosomes with peak concentration at 103 nm	ultracentrifugation	immature mouse dendritic cells	[195]
	curcumin and superparamagnetic iron oxide nanoparticles (SPIONs)	neuropilin-1 (NPR-1)-specific peptide RGE	RGE-mediated target to tumor site SPIONs-mediated magnetic flow hyperthermia (MFH) and curcumin	inhibit tumor growth and imaging by external magnetic field	glioblastoma	Exosomes 50–150 nm	ultracentrifugation	Raw 264.7 cells	[196]
	doxorubicin (Dox)	superparamagnetic nanoparticles (SPMNs)	SPMNs-mediated target to tumor site under an external magnetic field	inhibit tumor growth	hepatoma	Exosomes 40 to 110 nm	superparamagnetic magnetite colloidal nanocrystal clusters (SMCNCs)	pre-dialyzed serum	[197]
	doxorubicin (Dox)	superparamagnetic iron oxide nanoparticles (SPIONs) and anti-A33 antibody	anti-A33 antibody- and SPIONs- mediated target to tumor site and Dox	inhibit tumor growth with reduced cardiotoxicity	colorectal cancer	Exosomes 85.1 ± 1.5 nm	ultracentrifugation	Raw 264.7 cells	[198]
gene therapy	CRISPR/Cas9 targeting poly (ADP-ribose) polymerase-1 (PARP-1)	cancer cell-derived naïve tropism	suppress expression of PARP-1	induced tumor cell apoptosis and enhanced chemosensitivity to cisplatin	ovarian cancer	Exosomes 50–150 nm	ultracentrifugation	HEK 293 and SKOV3 cells	[199]
	phosphatase and tensin homologue (PTEN) mRNA	____	restore PTEN expression in PTEN-deficient glioma mouse models	inhibit tumor growth	glioma	Exosomes 70–110 nm	ultracentrifugation	mouse embryonic fibroblasts (MEFs)	[200]
	siRNA or shRNA targeting KrasG12D	____	CD47-mediated evasion from phagocytosis and suppression of KRASG12D expression	inhibit tumor growth	pancreatic cancer	Exosomes about 100 nm	ultracentrifugation	fibroblast-like mesenchymal cells	[201]
	siRNA targeting survivin	folate or PSMA RNA aptamer or EGFR RNA aptamer	suppress expression of survivin and tumor-specific aptamer-mediated target to tumor site	restored tumor cell apoptosis	prostate cancer breast cancer colorectal cancer	EVs about 96 nm	ultracentrifugation	HEK 293T cells	[202]
	siRNA targeting S100A4	cationic bovine serum albumin (CBSA)	suppress expression of S100A4	suppression of cancer metastasis	triple-negative breast cancer (TNBC)	Exosomes 124 ± 1.76 nm	gradient centrifugation	autologous breast cancer cells	[203]
	miR-206	bone marrow mesenchymal stem cell (BMSC)-derived naïve tropism	upregulation of miR-206 and suppressed expression of transformer 2β (TRA2B)	induced tumor cell apoptosis	osteosarcoma	Exosomes about 100 nm	ultracentrifugation	bone marrow mesenchymal stem cells (BMSCs)	[204]
	miR-26a	____	upregulation of miR-26a and suppressed expression of key proteins regulating the cell cycle	inhibit tumor growth and migration	Hepatocellular carcinoma	Exosomes 120 ± 9.7 nm	exosome isolation kit exoEasy™	HEK 293T cells	[205]
	miR-126	integrin β4 targeting surfactant protein C (SPC)	interrupt the PTEN/PI3K/AKT pathway	inhibit cancer metastasis	non-small cell lung carcinoma (NSCLC)	Exosomes 30–120 nm	centrifugation and PureExo® exosome isolation kit	MDA-MB-231 breast cancer cell	[206]
	miR-146b	mesenchymal stromal cell (MSC)-derived naïve tropism	suppress expression of EGFR	inhibit tumor invasion and migration	glioma	Exosomes 50–100 nm	centrifugation or sucrose gradients	bone marrow mesenchymal stem cells (BMSCs)	[207]
	miR-142a	mesenchymal stromal cell (MSC)-derived naïve tropism	silence Forkhead box (FOX) A2 and aberrant intracellular lipid accumulation	inhibit tumor growth	glioma	Exosomes 50–100 nm	centrifugation or sucrose gradients	bone marrow mesenchymal stem cells (BMSCs)	[207]
	let-7a	EGFR-specific GE11 peptide	upregulation of let-7a and affect previously unidentified or uncharacterized genes but not HGMA2 and RAS	inhibit tumor growth	breast cancer	Exosomes about 100 nm	differential centrifugation	HEK 293 cells	[208]
	gelonin	____	trigger cell apoptosis by cleaving a specific glycosidic bond in rRNA and disrupt protein synthesis	inhibit tumor growth	breast cancer	EVs mostly below 100 nm	ultracentrifugation	human breast adenocarcinoma MDA-MB-231 cells	[209]
	siRNA targeting SOX2	tLyp-1 peptide targeting neuropilin1 (NRP1) and neuropilin2 (NRP2)	knock down of SOX2 gene and reduce the stemness of cancer stem cells (CSCs)	inhibit tumor growth	non-small cell lung carcinoma (NSCLC)	Exosomes about 100 nm	differential centrifugation and micro-filtration	HEK 293T cells	[210]
	photosensitizer Ce6	Au nanoparticles	Ce6 exhibits near-inflared fluorescence for real-time imaging and generate abundant amount of singlet oxygen (1O2)	induce tumor cell apoptosis	gastric cancer	Exosomes 77.2 ± 33 nm	ultracentrifugation	first-morning-void urine from gastric cancer patients	[211]
	photosensitizer PplX	____	the first-stage light trigger the photochemical internalisation (PCI) and the second-stage light trigger generation of ROS	inhibit tumor growth	breast cancer	Exosomes about 114 nm	ultracentrifugation	murine mammary carcinoma (4T1) cells	[212]
photodynamic therapy (PDT)	photothermal agents (PTAs)	nucleus-target TAT peptide and membrane-target peptide RGD and vanadium carbide quantum dots (V2C ODs)	realize low-temperature PTT without limitation of penetration depth of PTAs and thermoresistance caused by heat shock protein (HSP)	inhibit tumor growth	breast cancer	Exosomes about 71 nm	total exosome isolation kit	MCF-7 cells	[213]
immunotherapy	monoclonal antibodies specific for CD3 and EGFR	monoclonal antibodies specific for CD3 and EGFR	sEVs with monoclonal antibodies specific for CD3 on T cells and EGFR on cancer cells recruit T cells to tumor sites and activate cytotoxic T cells	activate T cell responses	breast cancer	Exosomes about 100 nm	differential centrifugation	Expi293F cells	[214]
	monoclonal antibodies specific for CD4 and HER2	monoclonal antibodies specific for CD3 and EGFR	sEVs with monoclonal antibodies specific for CD3 on T cells and HER2 on cancer cells recruit T cells to tumor sites and activate cytotoxic T cells	activate T cell responses	breast cancer	Exosomes with a size distribution peaking at 109 nm	differential centrifugation and ultracentrifugation	Expi293F cells	[215]
	TNF-α ligands	cell-penetrating peptide (CPP) and superparamagnetic iron oxide nanoparticles (SPIONs)	interaction of TNF-α to receptor TNFR I and induction of the TNFR I-mediated apoptotic pathway	induce tumor cell apoptosis	melanoma	Exosomes mostly below 100 nm	ultracentrifugation	marrow mesenchymal stem cells (MSCs)	[216]
	signal regulatory protein α (SIRPα) variants	____	SIRPα variants disrupt CD47-SIRPα interaction and eliminate phagocytosis of tumor cells by macrophages	enhance tumor cell phagocytosis	colorectal cancer	Exosomes mean 100 nm	differential centrifugation	HEK 293T cells	[217]
gene therapy and chemotherapy	anti-miR-214 and cisplatin	____	down-regulation of miR-214 and reverse chemoresistance to cisplatin	reverse chemoresistance and inhibit tumor growth	gastric cancer	Exosomes about 100 nm	ultracentrifugation and total exosome isolation kit	HEK 293T cells	[218]
	anti-miR-21 and 5-FU	cancer cell-derived naïve tropism	down-regulation of miR-21 in 5-FU resistant tumor cells rescued PTEN and hMSH2 expression	reverse chemoresistance and induce tumor cell apoptosis	colorectal cancer	Exosomes 110 ± 11.3 nm	ultracentrifugation	HEK 293T cells	[219]
	siRNA targeting BCR-ABL and imatinib	IL-3 fragment	IL-3-mediated target; suppressed expression of Bcr-Abl protein; reversed binding of the imatinib	reverse chemoresistance and inhibit tumor growth	chronic myeloid leukemia (CML)	Exosomes 30–60 nm	ultracentrifugation	HEK 293T cells	[220]
	anti-miR-21 and Dox and gold iron oxide nanoparticles (GIONs)	cancer cell-derived naïve tropism and GIONs	down-regulation of miR-21 both imaging and PTT effect of GIONs	inhibit tumor growth	breast cancer	EVs about 100 nm	ultracentrifugation	4T1 cells	[221]

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ISSN: 1756-9966

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