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Page 6 of 10 Schulze et al. J Cancer Metastasis Treat 2020;6:42 I http://dx.doi.org/10.20517/2394-4722.2020.79
[86]
Interestingly, O’Brien et al. used engineered mesenchymal stem cells to secrete exosomes enriched
with miR-379 for in vivo therapy of breast cancer. Importantly, they found that systemic administration
of miR-379 enriched exosomes can significantly reduce tumor activity. Another miRNA, miR-145-5p,
was also found to inhibit pancreatic ductal adenocarcinoma cell proliferation and invasion, as well as
increased apoptosis. Moreover, exosomes transfected with miR-145-5p were able to inhibit pancreatic
[87]
ductal adenocarcinoma cell proliferation and invasion through TGF-β/Smad3 pathways . On the other
hand, inhibitors of exosomal miRNAs, which play key roles in cancer progression through exosome, have
become another effective method for cancer therapy. For example, exosomal miR-25-3p is a metastasis-
promoting miRNA of colorectal cancer. Exosomes enriched with miR-25-3p dramatically promoted
vascular permeability and colorectal cancer metastasis in mice liver and lung. Nevertheless, these effects
[88]
can be rescued by blockage of exosomal miR-25-3p by a miR-25-3p inhibitor .

Exosomes as protein carrier for cancer therapy
Recently, many scientists have begun to develop an exosomal-based cancer vaccine [89-91] . For example,
TNF-alpha-related-apoptosis-inducing-ligand (TRAIL), a cytokine, functions as a ligand that induces
[94]
cell apoptosis [92,93] . Rivoltini et al. reported that TRAIL-armed exosomes could promote apoptosis in
cancer cells and control tumor progression in vivo. Furthermore, IL-18 enriched exosomes enhance Th1
cytokine release and proliferation of peripheral blood mononuclear cells, suggesting that IL-18 enriched
exosomes harbor more capability to induce specific anti-tumor immunity as they trigger a bigger immune
[95]
[96]
response . Yang et al. also found that IL-2 enriched exosomes induce the antigen-specific Th1-polarized
immune response and cytotoxic T lymphocyte response more efficiently, leading a significant inhibition
of tumor growth in mice. Exosomes can also be used as carriers of protein antagonists. For example,
signal regulatory protein α (SIRPα) can interact with CD47, a “don’t eat me” signal that limits the ability
of macrophages to engulf tumor cells. Exosomes carrying SIRPα antagonists could significantly increase
[97]
tumor phagocytosis, as has been observed in tumor-bearing mice .
Exosomes as chemotherapeutic drug carriers for cancer therapy
Anti-tumor chemotherapeutic drugs can effectively kill fast-growing tumor cells. However, these drugs
can also kill the normal, healthy cells that are fast-growing, causing serious side effects. Besides, for
some hydrophobic drugs, it is a challenge for them to target tumor cells with any kind of specificity.
Therefore, an effective carrier for these drugs is badly needed. Due to their naturally derived origin and
their stable lipid bilayer structure, exosomes have the great potential to serve as an effective carrier for
[98]
chemotherapeutic agents. As early as 2012, Tang et al. reported that tumor cell-derived microparticles
can be used as chemotherapeutic drug carriers. They found that chemotherapeutic drugs loaded onto
[98]
[99]
microparticles had a potent anti-tumor effect both in vitro and in vivo . In 2015, Kim et al. developed a
exosome-based formulation of paclitaxel (PTX), a commonly used chemotherapeutic agent, to overcome
multiple drug resistance (MDR) in cancer cells. Three methods including incubation at room temperature,
electroporation, and mild sonication were used to incorporate PTX into exosomes; among which, the mild
[99]
sonication method resulted in the highest loading efficiency and sustained drug release . PTX-loaded
[99]
exosomes (exoPTX) increased cytotoxicity more than 50 times in drug resistant MDCK MDR1 (Pgp +) cells .
[99]
Furthermore, through a similar in vivo mice model, Kim et al. found that exoPTX can efficiently target
cancer cells and produce strong antineoplastic effects in mice with lung metastases. Similarly, Saari et al.
[100]
also found that delivery of PTX via cancer cell-derived exosomes enhances the cytotoxicity of PTX in
autologous prostate cancer cells. Furthermore, by modifying the exosome surface proteins, exosomes can
[101]
deliver chemotherapeutic drugs to cancer cells with a high degree of specificity. For example, Tian et al.
engineered Lamp2b-iRGD peptide (αv integrin-specific) expressing mouse immature DCs (imDCs),
isolated their exosomes and used them to deliver doxorubicin (Dox). Using this approach, they found that
iRGD-exosomes can efficiently target and deliver Dox to αv integrin-positive breast cancer cells in vitro,
[101]
and specifically to tumor tissues, resulting in inhibition of tumor growth in vivo .