Engineered Extracellular Vesicles in Cancers and Cardiovascular Diseases

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Changhai Tian	--	3475	2023-10-23 14:35:53	\|
2	layout	Jessie Wu	+ 2 word(s)	3477	2023-10-24 03:15:32	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms242015206

Extracellular vesicles (EVs) are small, membrane-bound vesicles used by cells to deliver biological cargo such as proteins, mRNA, and other biomolecules from one cell to another, thus inducing a specific response in the target cell and are a powerful method of cell to cell and organ to organ communication, especially during the pathogenesis of human disease.

engineered extracellular vesicles therapeutic applications heart failure cancer

1. Engineered Extracellular Vesicles in Cancers

Because of their unique ability to act as a delivery vehicle in vivo, extracellular vesicles (EVs) pose as excellent potential therapeutic agents for cancer treatment; many researchers have looked into this potential, and excitingly, the research is proving promising. EVs derived from cancer cells naturally exhibit a cancer-cell homing ability but oftentimes contain cargo that is beneficial to the tumor. Thus, the natural cargo can be removed via electroporation but the tumor-homing ability is maintained and the desired cargo may be added ^[1]. Various cancer cell types overexpress the integrins αv and β3/β5 both within the tumor and within their vasculature ^[2], which makes them useful as a potential target for EVs to hone to, and thus the RGD peptide was created ^[3]. This peptide is relatively easy to conjugate to the EVs through a simple click-chemistry reaction ^[4], making it a suitable choice for translational applications both from a therapeutic and logistical standpoint. Membrane cloaking is another method of increasing the targeting efficiency of EVs; that is, the addition of cell-type or tissue-specific targeting units to the membrane of the EV with the addition of an anchor. Although it is not yet widely researched, cloaked EVs exhibit an increased uptake efficiency, and the target cell is much more likely to uptake cloaked EVs ^[5]. EVs have already shown promising potential as therapeutic delivery vehicles for numerous cancers, several of which will be discussed hereafter. Incredibly, none of the researchers in these studies found any toxicity due to the EVs as the mice treated.

For example, glioblastoma (GBM) is arguably the deadliest of all human cancers, and most professionals currently believe it to be incurable ^[6]. However, it responded significantly to treatment with engineered EVs. In a study by S. Hong et al. in 2021, they found that by engineering EVs to carry miRNA-124, they were able to lower the expression of an anti-apoptotic marker and a proto-oncogene, mcl-1 and c-Myc, respectively. Thus, the apoptosis rate increased in GBM tumor cells, and the proliferation rate decreased. ^[7]. However, another study on miRNA-124 found that it prolonged the lifetime of M2 macrophages—the anti-inflammatory variant—and inhibited the M1 phenotype of macrophage—the variant that is aggressively anti-cancer ^[8]—which highlights the necessary precision of engineered EVs to target a specific cell type so as not to cause adverse effects. Another group of researchers looked into the potential of EVs to target GBM tumor cells using a targeting peptide known as c(RDGyK), a cyclic version of the standard αvβ3 integrin targeting ligand ^[9], and found it was easy to introduce to the EV ^[10]. EVs engineered to carry anti-PD-L1 siRNA were delivered to the GBM tumor, with researchers looking to decrease the levels of PD-L1 because this ligand, aptly named the programmed death ligand, allows cancer cells to slip past the immune system and avoid apoptosis ^[10]^[11]. When in combination with radiotherapy which increased uptake of EVs by the tumor, EVs successfully increased the number of anti-tumor CD8⁺ T cells and greatly extended the median survival time of mice with GBM tumors ^[10]. Success with anti-PD-L1 has also been found with the loading of metformin, a drug typically used to treat high blood glucose, into macrophage-derived EVs which then degrades the collagen of the tumor and renders it more likely to infiltration by CD8⁺ T cells ^[12].

Furthermore, gynecological cancers are of great interest as they lead to the mortality of many women around the globe. For example, because there is no prevention measure for ovarian cancer and screening is not commonplace nor high in accuracy, it is often found once it is in its advanced stages and already causing a host of symptoms for the patient ^[13]. Thus, many researchers have studied the potential of engineered EVs as therapeutic agents for ovarian cancer. When these EVs were engineered to express the tumor-homing RGD tag, there was an even more profound decrease in angiogenesis of the tumors, thus indicating that RGD helps the receiving cell to uptake the cargo from the tagged EV more efficiently and effectively. These tumor-homing EVs were loaded with miR-92b-3p and successfully suppressed the angiogenesis of the tumors ^[14]. miR-92b-3p acts as a tumor suppressor by inhibiting the expression of GABRA3, a transporter that is known to have abnormal expression in breast, pancreatic, and lung cancer ^[15]^[16]; it may also be abnormally overexpressed in other types of cancers, meaning that miR-92b-3p loaded into EVs could have translational applications for more than just one type of cancer. Another group of researchers looked into the anti-tumor effects of miR-199a-3p loaded into EVs for the treatment of ovarian cancer. They used non-targeted EVs engineered to carry miR-199a-3p, which is traditionally downregulated in several types of cancer compared to non-cancerous cells and is known to cause G1 phase arrest and upregulate c-Met ^[17]^[18]. It is also believed to upregulate mTOR. When all of these effects are combined, they produce a powerful anti-cancer effect that inhibits cancer cells and renders them more vulnerable to chemotherapeutic drugs ^[19]. Additionally, miR-199a-3p-loaded engineered EVs significantly inhibited the growth of ovarian cancer cells, thus decreasing the invasiveness of the tumor ^[17]. A very recent study suggests that hydrogel-loaded EVs derived from M1 macrophages transfected with Siglec10 are powerful tools for the treatment of ovarian cancer. These EVs successfully suppressed efferocytosis, thus allowing for increased antigen presentation to the now increased levels, due to the EVs, of M1 phenotype macrophages ^[20].

Furthermore, these hydrogel-loaded EVs have also been shown to be effective in treating triple-negative breast cancer (TNBC) that overexpresses CD24 by creating an anti-tumor microenvironment ^[20]. While breast cancer does have effective regular screening methods, unlike ovarian cancer, the survival rate is still poor, especially for women suffering from TNBC ^[21]. To treat this type of breast cancer with EVs, engineering them to express Hiltonol-ELANE-α-LA (HELA), in which ELANE is the ICD inducer human neutrophil elastase and α-LA is α-Lactalbumin, a protein expressed in the breast during many breast cancers, was highly effective to increase the targeting of the EVs ^[22]. To target other breast cancer cells, the epidermal growth factor receptor (EGFR) could be utilized, as this is overexpressed in some breast cancer cell types. However, a challenge arises in that the targeting peptide must target EGFR but not induce mitosis like the innate ligand epidermal growth factor (EGF). There is a ligand that can be used to target EGFR without causing the mitosis effect inherent of EGF. This peptide sequence, YHWYGYTPQNVI, is known as GE11 and was able to successfully be engineered onto HEK293 EVs ^[23]. EVs may also be fused with liposomes to create a hybrid delivery vehicle and engineered to express anti-EGFR antibodies so that they effectively target breast cancer cells ^[1].

Moreover, when EVs were tagged with HELA and loaded with a breast cancer drug, they effectively inhibited tumor growth in TNBC, even more so than when the drug was delivered freely by itself ^[22]. Interestingly, in breast cancer cells, the miR-205 is severely under-expressed, leading to increased cancer cell proliferation and greater ease of metastasis for cancer cells as miR-205 regulates cell growth. EVs engineered to contain miR-205 caused a greater number of cancer cells to be in apoptosis and fewer cancer cells to be viable through the decreased expression of an anti-apoptotic gene Bcl-2 ^[24]. It is probable that if miR-205, which targets the anti-apoptotic gene Bcl-2, was loaded into EVs engineered with the HELA tag, it would be especially effective in treating TNBC cells, but this research has yet to be performed. EVs tagged with the GE11 peptide to target breast cancer cells expressing EGFR were loaded with miRNA let-7a and significantly inhibited the proliferation of the cancer cells through a poorly understood pathway ^[23]. More research should be performed on the mechanism by which miRNA let-7a inhibits cancer cell proliferation and the effect that it may have when administered in tandem with miR-205 in the treatment of breast cancer. However, as miRNA let-7a downregulates c-Myc, a proto-oncogene ^[7], expression in other cancers ^[25] leading to chemoresistance and increased tumor aggression ^[26], it may perform in the same way during breast cancer, leading to the results found by Ohno et al. Doxorubicin (Dox), when loaded into immature dendritic cell-derived EVs tagged with the iRGD peptide was also successful in targeting breast cancer cells and greatly inhibiting tumor growth without toxicity to normal cells ^[27].

Additionally, as the third leading cause of death in women worldwide, new treatments for cervical cancer are of great interest ^[28]. When bone marrow mesenchymal stem cell (MSC)-derived EVs were loaded with miR-375, they decreased the proliferation, migration, and invasion capabilities of the cancer cells while simultaneously increasing apoptosis in the cells ^[29]. In gastric cancer, increased levels of miR-375 lead to ferroptosis ^[30], which may be the mechanism by which the engineered EVs loaded with miR-375 were able to increase apoptosis in the cervical cancer cells. When tested on mice xenografted with cervical cancer tumors, the engineered EVs decreased the tumor volume and the number of migrated, invaded, and proliferative cells while simultaneously increasing the number of apoptotic cervical cancer cells ^[29]. If miR-375 promotes apoptosis by inducing ferroptosis in cervical cancer as it does in gastric cancer, translational approaches involving EVs engineered to carry miR-375 may benefit from additional iron, either by supplement or directly loaded into the EVs themselves, or from EVs loaded with Erastin, a ferroptosis inducer ^[31]. Naturally, more research is required in this area, especially as the authors could not find evidence of metal loaded into EVs, except for the successful delivery of iron oxide through engineered EVs to a mouse brain ^[32].

Furthermore, malignant melanoma poses a severe threat to all persons, especially those of darker skin tones; for them, it is often not discovered until it is in an advanced stage ^[33]. There has also been a dramatic increase in the incidence of melanoma, and as it is the cause of more than 85% of skin cancer-related deaths, it is vital to find new therapeutics ^[34]. MSC-derived EVs engineered to bind to the αvβ3 integrin—an integrin overexpressed in many tumor types—successfully targeted melanoma tumor cells and avoided the liver. Additionally, they were able to slow down the rate of mitosis, promote apoptosis, and suppress invasion of the tumor cells ^[35]. EVs derived from melanoma cell lines engineered to carry miR-195-5p, which is known to regulate key malignancies of tumor cells ^[36], were effective in decreasing the proliferation of treated melanoma cells by increasing hypodiploid cells likely through the pathway of one of the 41 miRNAs that experienced changed expression due to treatment with the EVs ^[37].

Sadly, as the second leading cause of death from cancer around the globe, gastric cancer still poses a considerable threat to public health. EVs were engineered to carry the RNA cargo circDIDO1, which increased the expression of SCOS2 in treated cancer cells, leading to a substantial decrease in cancer cell proliferation rate and development. Many treated cells underwent apoptosis due to the RNA cargo ^[38], likely because SCOS2, which exhibited increased expression, is known to be a vital aspect of cell growth through the GH/IGH-1 signaling pathway ^[39]. EVs engineered to deliver circDIDO1 were successful in inhibiting gastric cancer progression via increased SCOS2 expression, and other types of cancers may benefit from these EVs as well because SOCS2 downregulation is common for many types of cancer; however, EVs loaded with this cargo do not pose a therapeutic use towards leukemia as SOCS2 is already overexpressed in those cancer cells ^[40]. Nevertheless, this research by Guo et al. highlights the powerful effects of RNA-loaded EVs, while at the same time pointing to the immense research that must be conducted to avoid any adverse side effects.

Posing another severe threat to public health, colon cancer has a five-year survival rate of just 52% ^[41]. EVs were engineered with the target-Her2-LAMP2-GFP (THLG) targeting unit that targets the Her2 protein commonly overexpressed in colon cancer cells. When loaded with miR-21 and 5-FU, a chemotherapeutic drug used to treat colon cancer, EV treatment exhibited a significant increase in the number of tumor cells in apoptosis, and cell proliferation decreased by 82%. Interestingly, the mechanism of this arrest was during the S phase of the cell cycle ^[42]. Even more intriguingly, miR-21 is overexpressed in ovarian cancer cells. In that cell line, when suppressed, it causes apoptosis of cancer cells while decreasing their proliferation; this is through the PTEN/PI3K/AKT pathway ^[43]. However, it is also involved in cancer cells gaining resistance to chemotherapeutics ^[44], likely the mechanism of action found in Liang et al.’s study. Furthermore, when Liang et al. injected mice with colon cancer tumors with these EVs, there was no significant decrease in body weight, but there was a remarkable decrease in tumor weight and inhibition of tumor growth ^[42].

Additionally, the incidence of pancreatic cancer is increasing, and with over 430,000 pancreatic cancer-related deaths in 2018, the development of new therapeutics is vitally important ^[45]. Like many other types of tumors, pancreatic tumors often overexpress the αvβ3 integrand targeted by the RGD peptide. Thus, EVs engineered to have the RGD peptide attached and filled with the common pancreatic cancer drug paclitaxel cause significantly decreased tumor growth compared to free-drug delivery. The cells treated with the EVs loaded with paclitaxel were more likely to go into apoptosis than even those treated with free paclitaxel ^[46]. The homing ability of the EVs with the RGD targeting peptide increased the efficiency and effectiveness of the paclitaxel delivery, indicating that loading chemotherapeutic drugs into EVs could have immense translational applications.

Moreover, liver cancer poses low five-year survival rates at under 50% for all age groups and genders ^[47]. HepG2 cells, a type of liver cancer cell, overexpress the SR-B1 receptor that interacts with the protein Apo-A1. SR-B1 also exhibits overexpression in many other tumor-associated vascular endothelium. Thus, to target these HepG2 cancer cells using EVs, the researchers added the Apo-A1 protein on the surface of the EV. This targeting protein increased the targeting itself and the ease with which the recipient cell could take up the EV because the binding of the protein triggered receptor-mediated endocytosis of the EV. When researchers loaded these engineered EVs with miR-26a, the target cells exhibited decreased migratory abilities ^[48]. miR-26a is known to inhibit the proliferation of both thyroid and prostate cancer cells through the targeting of ARPP19 and CDC6, respectively, both of which are genes controlling cell cycle progression ^[49]^[50]^[51]^[52], thus indicating that miR-26 likely interacted with either of these gene products—or perhaps another, yet unknown cell cycle regulator—to produce the anti-migratory abilities found in the study on liver cancer by Liang et al. ^[48]. Ferroptosis may also be induced in liver cancer cells when they are treated with EVs loaded with CD47, Erastin—a ferroptosis inducer—and Rose Bengal—a photosensitizer—followed by laser irradiation ^[31].

Even more devastatingly, osteosarcoma, a type of bone tumor, is especially prevalent in children and adolescents, often requiring chemotherapy and surgery to treat ^[53]. Long-noncoding RNA Maternally Expressed Gene 3 (lncRNA MEG3), which functions as a sponge for miRNAs ^[54], is under-expressed in osteosarcoma tissues ^[55]. Researchers loaded EVs engineered to target the αvβ3 integrin through the engineered expression of the cRGD peptide with lncRNA MEG3, and they successfully targeted osteosarcoma cells in vivo. The engineered EVs induced increased apoptosis of the cancer cells and decreased migration and proliferation. The researchers believed this result was likely due to the sponging effect of lncRNA MEG3 on miR-185-5p ^[55]. While their results do show inhibited tumor growth, miR-185-5p, when upregulated, prevents the proliferation of leukemia cells while at the same time promoting apoptosis ^[56], which is the opposite of what is suggested by Huang et al. Thus, more research must be carried out before loading lncRNAs into EVs, as their effects on each type of cancer must be well understood before their therapeutic effects can become widely applied. Nevertheless, lncRNAs have a relatively recently discovered complex role in cancer development and regulate transcription on a cell-specific basis ^[57]; thus, the ability to directly deliver them to specific cell types using engineered EVs poses great promise for translational applications.

Additionally, engineered EVs are also poised to be an excellent therapeutic tool to sensitize cancer cells to radiotherapy. In one study, EVs derived from M1 phenotype macrophages were not only successful in polarizing both M2 and M0 phenotype macrophages to the anti-tumor phenotype M1 but also were successful in delivering radiotherapy sensitization cargo to tumor cells, thus increasing the level of apoptosis when treated with radiotherapy. Those EVs engineered with an anti-PD-L1 tag were most successful at targeting the tumor cells. Mice with tumors treated with these EVs exhibited significantly decreased tumor weight and a significant increase in survival time. However, the engineered EVs did not induce chronic inflammation or increase the side effects of the radiation ^[58]. Another study found that EVs engineered with the 131 isotopes of iodine and a targeting peptide were most successful in being cytotoxic to only cancer cells when loaded with the chemotherapeutic agent Dox. They exhibited good biosafety in mice and were well retained within the blood, allowing for a high level of accumulation within the tumor ^[59]. EVs may also be used to sensitive cancer cells to chemo-sonodynamic therapy through the loading of sonosensitizer agent Chlorin e6 and the addition of a mitochondrial targeting moiety triphenyl phosphonium ^[60]. The applications of Engineered EVs in developing cancer therapeutic strategies are summarized in Table 1.

Table 1. The applications of engineered EVs in cancer therapy.

Type of Cancer	Origin of EVs	Engineered strategy	Functional Cargo	Mechanism	Ref.
GBM	HEK293 T; human neural progenitor cells	Coincubation; click-chemistry	miR-124; anti-PD-L1 siRNA	Decreased expression of mcl-1 and c-Myc; decreased expression of PD-L1	^[7]^[10]
Ovarian Cancer	HEK293 T; fibroblasts; M1 macrophages	Transfection; electroporation; extrusion approach	miR-92b-3p; miR-199a-3p; efferocytosis inhibitor MRX-2843	Suppressed expression of GABRA3; cell cycle arrest, increased expression of c-Met and mTOR; suppression of efferocytosis	^[14]^[17]^[19]^[20]
Breast Cancer	Dendritic cells; MDA-MB-231; HEK293 T	Electroporation; transfection	Human neutrophil elastase (ELANE) and Hiltonol (TLR3 agonist); miR-205; miRNA let-7a; Dox	Antitumor immunity; chemotherapy; targeting of Bcl-2; downregulation of c-Myc	^[22]^[23]^[24]
Cervical Cancer	Bone marrow-derived MSC	Transfection	miR-375	Ferroptosis	^[29]
Melanoma	Melanoma cell lines	Transfection	miR-195-5p	Induced hypodiploidy	^[37]
Gastric Cancer	HEK293 T	Transfection	circDIDO1	Increased expression of SCOS2	^[38]
Colon Cancer	HEK293 T	Transfection; electroporation	miR-21 inhibitor; 5-FU	Cell cycle arrest; chemotherapy	^[42]
Pancreatic Cancer	PANC-1; U937	Coincubation; sonication	Paclitaxel	Chemotherapy	^[46]
Liver Cancer	HEK293 T	Transfection; sonication	miR-26a; CD47; Erastin; Rose Bengal	Targeting of ARPP19 and CDC6; ferroptosis; photosensitization	^[31]^[48]^[49]^[50]^[51]^[52]
Osteosarcoma	Osteosarcoma cells	Transfection	lncRNA MEG3	Sponging of miR-185-5p	^[54]^[55]

2. Engineered Extracellular Vesicles in Cardiovascular Diseases

Amazingly, EVs are useful for more than just cancer treatment. Targeting peptides, such as the sequence CSTSMLKAC, cause EVs engineered to express it to target not only cardiac tissue but specifically infarcted heart tissue ^[61]. Cardiac tissue likely has further difficulty receiving EVs than other tissue due to the layout of blood vessels in the tight junction cellular arrangement of the heart ^[62]. During a hypoxemic event, EVs are released by the heart containing different levels of specific mRNAs when compared to those released at normal oxygen levels. Interestingly, they innately target ischemic myocardial cells due to a peptide on their surface ^[63].

Moreover, by adding a cardiomyocyte targeting peptide to an EV containing a siRNA designed to down-regulate a gene involved in the apoptosis of cardiomyocytes, the degree of apoptosis in cardiomyocytes significantly decreased ^[62]. Furthermore, a study on the effect of EVs engineered to target cardiac cells after myocardial infarction in rats found that they were beneficial in increasing cardiac regeneration, likely due to the miRNA contents of the EVs ^[64]. Similarly, injected MSCs have been shown to home directly to ischemic heart tissue when engineered to have an additional cardiac homing peptide ^[65]. However, MSC-EVs have been shown to deliver the same benefits to myocardial cells undergoing repair as when MSCs are delivered into the heart, but do not carry the risk of becoming tumorigenic because they are not able to go through mitosis ^[66]. Similarly, when bone marrow-derived mesenchymal stem cell-derived EVs are loaded with atorvastatin, a drug used to prevent cardiovascular disease, and are administered to rodents after myocardial infarction, they significantly improve heart function and reduce the size of the infarct, even more so than just MSC-EVs alone ^[67]. These findings have implications for translational applications because it has been determined through this research that the mode of action for the benefits of transplanted MSCs is the EVs themselves ^[68], and when tested on healthy human fibroblast cells, it indicates that cardiac targeting peptide will be just as useful in humans as they are in mouse models ^[69]. However, human clinical trials have yet to be performed.

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Jessica N. Ziegler

Changhai Tian

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1. Engineered Extracellular Vesicles in Cancers

2. Engineered Extracellular Vesicles in Cardiovascular Diseases

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