Science - USA (2020-02-07)

their usefulness in early diagnosis ( 193 ). This
may be in part driven by the genomic land-
scape of cancer cells, with oncogenic Kras re-
ported to differentially enrich for miR-100 in
exosomes ( 194 ). Elevated circulating exosomal
miR-21 has been associated with glioblastomas
and pancreatic, colorectal, colon, liver, breast,
ovarian, and esophageal cancers, and elevated
urine-derived exosomal miR-21 has been asso-
ciated with bladder and prostate cancer [re-
viewed in ( 193 , 195 )]. Other exosomal oncogenic
microRNAs associated with multiple cancer
types include miR-155, the miR-17-92 cluster,
and miR-1246 ( 196 – 199 ). These are noted to be
up-regulated in cancers of the brain, pancreas,
colorectum, colon, liver, breast, prostate, and
esophagus; in oral squamous cell cancer; as well
as in lymphoma and leukemia ( 193 ). Tumor-
suppressor miRNAs, including miR-146a and
miR-34a, are associated with liver, breast, colon,
pancreatic, and hematologic malignancies ( 193 ).
The combination of multiple microRNAs may
enhance the diagnostic and prognostic po-
tential of exosomal miRNA, and exosomal miR

signatures are continuously emerging in as-

sociation with cancer diagnosis and progno-

sis ( 195 , 200 – 204 ). The diagnostic potential of

phosphoprotein in circulating exosomes from

breast cancer patients has also been reported

( 205 ), as well as exosome surface protein analy-

ses ( 206 ). Several independent laboratories have

reported the utility of GPC1 (glypican 1)–positive

exosomes in the diagnosis of pancreatic, breast,

and colon cancer, with GPC1 being enriched

in cancer cell–derived exosomes, thus enabling

the detection of cancer and possibly response

to therapy (decrease in exosome numbers and

thus tumor burden) ( 207 – 216 ). Immunocapture

strategies are also under investigation to detect

circulating cancer exosomes using surface CD147

expression in patients with colorectal cancer

( 217 ). The relative PtdSer composition of exo-

somes may also prove useful for the early detec-

tion of cancer in mice, as evaluated from the

serum of mice bearing breast or pancreatic tu-

mors ( 218 ). The possibility of combining pro-

tein, lipid, RNA, and miRNA exosomal cargos

in cancer diagnosis andprognostic evaluation

is currently being considered. A multicompo-

nent, combinatorial approach using a combi-

nation of markers that reflect distinct aspects

of disease-generating exosomes (e.g., metab-

olite, RNA, and protein content) could poten-

tially enhance the specificity and sensitivity of

an exosome-based diagnostic. Such efforts

would be more likely to identify collective

disease-specific changes, and lipid bilayer en-

capsulation could preserve enzyme-sensitive

molecular cargos.

Therapeutic potential of exosomes

Exosomes by themselves or as vehicles for the

delivery of drug payload(s) are being actively

explored as therapeutic agents (Fig. 6). In con-

trast to liposomes, injected exosomes are ef-

ficient at entering other cells and can deliver

a functional cargo with minimal immune

clearance upon exogenous administration in

mice ( 2 , 181 , 219 – 221 ). In addition, the ther-

apeutic application of exosomes is promising

because they have been demonstrated to be

well tolerated. Exosomes from mesenchymal

Kalluriet al.,Science 367 , eaau6977 (2020) 7 February 2020 10 of 15

Fig. 6. Cellular uptake
of therapeutic exo-
somes.Therapeutic
exosomes isolated
from dendritic cells,
fibroblasts, and mes-
enchymal cells can
impart specific effects
on the target cells,
including neoantigen
presentation, immuno-
modulation, and drug
payload delivery. The
impact of therapeutic
exosomes on target
cells may be controlled
by the different mech-
anisms of entry or
interaction. Entry of
intact exosomes
can involve receptor-
mediated endocytosis,
clathrin-coated pits,
lipid rafts, phagocyto-
sis, caveolae, and
macropinocytosis.
Entry of the content of
the exosomes, or
induction of signals by
exosomes, can involve
ligand-receptor–
induced intracellular
signaling or fusion to
deposit the contents of
the exosomes into the
cytoplasm. Examples of
therapeutic payload are
listed. Target cells include cancer cells, injured parenchymal cells, and immune cells. ASO, antisense oligonucleotide (a DNA oligo-binding RNA target).

En

try

of

int

ac

tex

os

om

es

Therapeutic exosomes

Dendritic cells

Immunomodulatory

Neoantigen preparation

and delivery

Carrier of payloads

Fibroblasts and

other cell lines Carrier of payloads

Engineered for

immunoregulation

Mesenchymal

stem cells Immunomodulatory

Carrier of payloads

Receptor-mediated

exosomes entry

Intracellular

signalling

Receptor-mediated

endocytosis

Direct

binding

Clathrin-

coated pit

Lipid raft

Phagocytosis

Caveola

Macropinocytosis Direct fusion

Release of

exosome

contents

Nucleus

Therapeutic target cells

Cancer cells

Injured/abnormal

parenchymal cells

Immune cells

Examples of exosome payloads

miRNA

siRNA

ASO

Small molecules

Chemotherapeutics

Antibodies

Metabolites, etc.

mRNA

DNA

Proteins

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