Exosomes are naturally occurring extracellular nanovesicles
with a size range of 50–150 nm, and they are released by nearly
all cell types [15, 16]. Their biogenesis involves the endosomal
system and the formation of MultiVesicular Bodies (MVBs),
where exosomes mature and are enriched with key surface protein
markers (such as the endosomal sorting complexes required for
transport (ESCRT)-associated proteins (Alix and TSG101), heat
shock proteins (Hsp70 and Hsp90), and tetraspanins (CD9,
CD63, and CD81)) prior to their release into the extracellular
space [17–19].
As mediators of cell-to-cell communication in many physiological or pathophysiological conditions, exosomes are capable of
shuttling many biomolecular cargos (such as proteins, carbohydrates, lipids, and nucleic acids) intercellularly. Furthermore, due
to their natural origin, exosomes are proven to be much safer and
more biocompatible DDSs as compared to their synthetic counterparts [20]. Owing to the surface molecules (mainly proteins and
lipids) preserved from the parent cells, exosomes exhibit cellspecific targeting phenomena on certain recipient cells through
adhesion and subsequent uptake (by fusion or endocytosis/phagocytosis) [19, 21, 22], which highlights the possibility of employing
exosomes for targeted delivery. Indeed, exosomes have been
explored for loading of various therapeutics, including small molecules (e.g., paclitaxel [23], doxorubicin (Dox) [24], and curcumin
[25]), protein-based drugs (e.g., catalase [26]), and nucleic acids
(e.g., siRNA [27] and miRNA [28]).
Up to date, exosomes have been extensively investigated clinically. At the time of publication, there are 124 clinical studies listed
in US-NIH clinical trial database (https://clinicaltrials.gov/) with
the keyword search of “exosomes.” Although most of the clinical
studies are associated with biomarker identification and diagnosis/
prognosis of various diseases, we have summarized the studies
related to the use of exosomes as DDSs in Table 1.
Despite the promising results in vitro and in vivo, the clinical
translation of exosomes has been impeded by the inefficient extraction and tedious isolation process [20, 29]. Most of the exosome
extraction methods are complex, labor-intensive, and timeconsuming, yet the production yields are poor (Table 2). One of
the most common methods for the isolation of exosomes involves
ultracentrifugation or/and purification with sucrose density gradient. This process is time-consuming and requires large amount of
starting materials (e.g., cell culture medium and cells) to be able to
obtain sufficient amount of exosomes for cellular assays or in vivo
applications (e.g., 10
6 cells can only produce approximately 0.5 μg
of exosomes (in terms of protein content) [30]). Other methods,
such as gel-filtration, polymeric precipitation, or immunoaffinity
capture, have been reported to overcome the low production
Exosome-Mimetics For Drug Delivery
149
with a size range of 50–150 nm, and they are released by nearly
all cell types [15, 16]. Their biogenesis involves the endosomal
system and the formation of MultiVesicular Bodies (MVBs),
where exosomes mature and are enriched with key surface protein
markers (such as the endosomal sorting complexes required for
transport (ESCRT)-associated proteins (Alix and TSG101), heat
shock proteins (Hsp70 and Hsp90), and tetraspanins (CD9,
CD63, and CD81)) prior to their release into the extracellular
space [17–19].
As mediators of cell-to-cell communication in many physiological or pathophysiological conditions, exosomes are capable of
shuttling many biomolecular cargos (such as proteins, carbohydrates, lipids, and nucleic acids) intercellularly. Furthermore, due
to their natural origin, exosomes are proven to be much safer and
more biocompatible DDSs as compared to their synthetic counterparts [20]. Owing to the surface molecules (mainly proteins and
lipids) preserved from the parent cells, exosomes exhibit cellspecific targeting phenomena on certain recipient cells through
adhesion and subsequent uptake (by fusion or endocytosis/phagocytosis) [19, 21, 22], which highlights the possibility of employing
exosomes for targeted delivery. Indeed, exosomes have been
explored for loading of various therapeutics, including small molecules (e.g., paclitaxel [23], doxorubicin (Dox) [24], and curcumin
[25]), protein-based drugs (e.g., catalase [26]), and nucleic acids
(e.g., siRNA [27] and miRNA [28]).
Up to date, exosomes have been extensively investigated clinically. At the time of publication, there are 124 clinical studies listed
in US-NIH clinical trial database (https://clinicaltrials.gov/) with
the keyword search of “exosomes.” Although most of the clinical
studies are associated with biomarker identification and diagnosis/
prognosis of various diseases, we have summarized the studies
related to the use of exosomes as DDSs in Table 1.
Despite the promising results in vitro and in vivo, the clinical
translation of exosomes has been impeded by the inefficient extraction and tedious isolation process [20, 29]. Most of the exosome
extraction methods are complex, labor-intensive, and timeconsuming, yet the production yields are poor (Table 2). One of
the most common methods for the isolation of exosomes involves
ultracentrifugation or/and purification with sucrose density gradient. This process is time-consuming and requires large amount of
starting materials (e.g., cell culture medium and cells) to be able to
obtain sufficient amount of exosomes for cellular assays or in vivo
applications (e.g., 10
6 cells can only produce approximately 0.5 μg
of exosomes (in terms of protein content) [30]). Other methods,
such as gel-filtration, polymeric precipitation, or immunoaffinity
capture, have been reported to overcome the low production
Exosome-Mimetics For Drug Delivery
149