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Page 4 of 8 Panfoli et al. J Cancer Metastasis Treat 2020;6:35 I http://dx.doi.org/10.20517/2394-4722.2020.50
[53]
and proteins or as drug delivery system for cancer therapy . Drug delivery with Exo has been utilized
[54]
for the treatment of breast, pancreatic, lung, and prostate cancers and glioblastoma . Drug loading into
Exo can be accomplished by both active and passive encapsulation approaches [55,56] . Passive loading can
be accomplished by simple incubation of the Exo with the drug or miRNAs to let them diffuse along the
concentration gradient or treating cells with a drug, and using Exo secreted by these donor cells. Active
encapsulation can be performed by freeze-thawing cycles, electroporation of the Exo membranes, or
[56]
sonication in the presence of the drug . Sonication can be also used to encapsulate proteins. Freeze-
thawing method has also been utilized to fuse Exo with liposomes, to develop exosome-liposome hybrids
[57]
carrying specific proteins . By manipulating the shedding process of Exo, these can also be engineered
using viral vectors, such as retroviruses and adenoviruses to engineer the parent cells to secrete modified
Exo, or alternatively, to directly manipulate the content Exo following secretion [30,56] . The use of Exo also
shows significant safety and low toxicity benefits as compared to cell-based therapies, which bear the risk
[30]
of activation of a host immune response. By contrast, allogenic Exo elicit lower immune response . The
[58]
use of MSC-derived Exo for delivery of anticancer therapy was shown to hold more promise than the use
[11]
[59]
of MSC themselves . The fact that MSC Exo carry an aerobic metabolic ability may also be taken into
closer consideration.
Exo are also a promising new tool of cancer immunotherapy [15,60] . In lieu of dendritic cell (DC)-based cancer
immunotherapy, still in its infancy due to problems associated with culture and storage, the use of DC-
derived Exo to generate immune responses against tumours, has been proposed . DC-derived Exo possess
[31]
immunostimulatory properties thanks to the expression of integrins, ICAM-1 and MHC class II and class I
molecules as well. Exo stability would maintain the DC-derived Exo cancer antigen composition, including
surface MHC-peptide complexes and the CD80 and CD86 costimulatory molecules, thus triggering the
[31]
desired cancer antigen-specific immune response . DC-derived Exo-based phase I and II clinical trials
[61]
have demonstrated their ability to target cancer sites .
By genetic modification of the parental cell, Exo can be loaded with a variety of biological molecules, such
as miRNAs and proteins. Exo surface modification by addition of ligands or proteins to the Exo surface can
[32]
direct them to target cancer cells . In this respect, the features that allow Exo to reach their targets (i.e.,
ligands expressed onto their surface) allow their positive applications. Targeting ligands on the surface of
Exo can also be engineered. For example, HEK293T cells were engineered to express the protein Lamp2b,
fused to a fragment of interleukin 3 in their Exo membrane, and it was found that these Exo loaded with
imatinib or with a specific siRNA were able to target cancer cells and inhibit their growth in vitro and
[62]
in vivo . Exo released by macrophages, loaded with paclitaxel (PTX) increased the cytotoxicity of PTX by
about 50-fold. In vivo, those Exo co-localized with lung metastases causing a significant inhibition of their
growth .
[63]
The hallmark of the double nature of Exo is their ability to deliver miRNA, small noncoding RNAs that
target mRNAs and change their expression. Exo can be manipulated to have them deliver anti-miRNAs,
or tumour-suppressing miRNAs for cancer treatment. It was shown that endothelial cells can transfer
[64]
exogenous miRNA to cancer cells via Exo .

THE BAD SIDE OF EXOSOMES
[65]
Cancer cells secrete more Exo than healthy cells . Moreover, their contents appear to be tailored to
mediate cancer dissemination [8,16,17,23] . Being potent signalling mediators, Exo shed from cancer cells
act in facilitating cancer initiation and progression [20,21] . Exo are also secreted by cells in the tumour
microenvironment (TME) such as stromal and immune cells [22,66] . TME is the complex setting of the
interplay between cells and signalling events, of which Exo along with cytokines and chemokines are key
[8]
players . In particular, Exo can precondition the TME setting the pre-metastatic niche, which increases