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secreted by cells. These methods aim to enhance the therapeutic potential of exosomes
by incorporating specific drugs, proteins, nucleic acids, or other bioactive molecules.
Freeze-thaw cycling involves subjecting exosome samples to rapid freezing followed by thawing. This process helps to disrupt the integrity of the exosomes, allowing for enhanced cargo loading. During freezing, the exosome membrane becomes
more permeable, which facilitates the uptake of therapeutic cargo molecules. Sato
et al., demonstrated the utilization of freeze-thaw procedures to manufacture exosome-mimetic liposomal particles [31]. However, when compared to other methods
of drug encapsulation, freeze-thaw cycling can promote exosomal aggregation and is
often less successful than sonication or extrusion [24, 29].
Chemical transfection methods have been used to load exosomes with siRNA
as shown in several studies [32, 33]. This approach may not be suitable due to
a decreased loading efficiency as compared to electroporation. Furthermore,
the Lipofectamine 2000 reagent was shown to make micelles, which could have
impaired the quality of the exosomal preparation. Altogether, chemical transfection
of exosomes is inefficient for loading drugs into exosomes [23]. Transfection of
cells can indeed be used as a method for loading therapeutic cargo into exosomes.
In this approach, instead of directly loading the cargo into exosomes, the cargo
is introduced into the donor cells, which then release the cargo-loaded exosomes
[23]. This method involves transfecting the donor cells with the desired therapeutic
cargo, typically using transfection reagents or techniques such as electroporation.
In a recent study by Katakowski et al., bone marrow stromal cells were utilized to
transfect with miR-146b and resulting exosomes from these cells were isolated to
treat 9L gliosarcoma cells. The obtained exosomes from transfected cells revealed
increased miR-146b expression and has been shown to inhibit glioma development
in rat models [34].
. Role of exosomes in tumor microenvironment
The role of exosomes in the tumor microenvironment is a fascinating and rapidly
growing field of research [35, 36]. Exosomes are small extracellular vesicles that are
released by various cell types, including cancer cells, into the surrounding environment [37]. They play an important role in intercellular communication between
cancer cells and their tumor microenvironment, facilitating the exchange of molecular signals and genetic material, and have also been linked to a variety of physiological
and pathological processes, including cancer development and progression [35, 38].
The microenvironment, in the context of cancer, refers to the cellular and non-cellular components surrounding the tumor, including stromal cells, immune cells, fibroblasts, the extracellular matrix, blood vessels, basement membrane, and endothelial
cells [38]. These components actively interact with cancer cells and can influence
tumor growth, metastasis, and response to therapy. Considering all these factors/
components, there are four primary modes which exosomes from various sources can
alter the TME: through facilitating immunological escape, drug resistance, increasing
metastasis, and enhancing angiogenesis.
. Exploring the role of exosomes in immune evasion
Exosome-mediated immune evasion occurs when these vesicles are utilized by cancer cells and pathogens to escape immune surveillance [39, 40]. These entities exploit
Exosome-Based Smart Drug Delivery for Cancer Treatment
DOI: http://ITexLi.113744
exosomes to carry specific molecules that suppress the immune system, allowing them
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to evade detection and continue their malignant or infectious activities. The function
of T cells can also be inhibited by these exosomes, and there are numerous ways to do
this [41]. The activation of T cells’ immune systems to combat cancer cells is inhibited
in one approach by the binding of programmed cell death ligand 1 (PDL1) to PD1
receptors on T cell membranes [42]. They also contribute to immune evasion through
the transfer of immunosuppressive molecules. Cancer cells and pathogens package
molecules such as transforming growth factor-beta (TGF-β), interleukin-10 (IL-10),
and FasL into exosomes [43]. When these exosomes interact with immune cells, they
can inhibit the activation and function of T cells, natural killer cells, and dendritic
cells, subsequently undermining the immune response. Exosomes also participate in
the establishment of an immunosuppressive microenvironment. They can influence
the behavior of surrounding cells, including immune cells, by transmitting signals that
promote an environment conducive to immune evasion. For instance, tumor-derived
exosomes can induce the differentiation of regulatory T cells (Tregs), which suppress
immune responses and foster tumor growth [44]. Exosomes associated with tumors
have been shown to alter the phenotype of macrophages in multiple malignancies from
M1 (tumor resistance, pro-inflammatory) to M2 (tumor promotion, anti-inflammatory) [45–48]. As a result, exosomes derived from these altered M2 macrophages can
promote migration and invasion further. This was shown in a recent study by Lan
al., who investigated that macrophage-derived exosomes contained high levels of
et
miR-21-5p and miR-155-5p, which caused BRG1, a crucial component in colorectal
cancer metastasis, to be downregulated [49]. Figure
summarizes these effects.
Furthermore, exosome-mediated immune evasion can dampen the effectiveness
of immunotherapies [43]. Immunotherapeutic strategies aim to enhance the immune
system’s ability to recognize and eliminate cancer cells or pathogens [50]. However,
exosomes produced by these entities can interfere with this process. They can either
directly inhibit immune cells’ activity or carry molecules that counteract the effects
of immunotherapy. Understanding this phenomenon is vital for the development
of strategies to overcome immune evasion [51]. Researchers are exploring various
approaches, including targeting specific molecules carried by exosomes, modulating exosome release, or utilizing exosomes for therapeutic purposes. By unraveling
the mechanisms of exosome-mediated immune evasion, scientists hope to optimize
immunotherapies and improve the prognosis for patients affected by diseases
Figure 1.
Exosome-mediate tumor evasion.
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involving immune evasion mechanisms [43, 52]. Further research in this area promises to enhance our understanding of immune evasion mechanisms and pave the way
for innovative therapeutic interventions.
. Understanding how exosomes drive cancer progression
One important role of exosomes in the cancer-associated microenvironment is
their ability to promote tumor progression and metastasis. Exosomes released by
cancer cells can transfer oncogenic cargo (such as growth factors, cytokines, miRNA
proteins, RNA, DNA, and lipids) to recipient cells in the microenvironment, altering
their behavior and promoting a pro-tumorigenic state. Exosomes have been shown to
promote EMT, stimulate cell growth, and even disrupt the ECM to facilitate invasion
and metastasis from the initial site to distant sites in the body [53]. Furthermore,
exosomes can confer invasive properties to cancer cells, leading to enhanced metastasis. Exosomes released by primary tumor cells can prepare distant sites for metastatic
colonization by promoting pre-metastatic niche formation. They achieve this by
influencing the extracellular matrix, remodeling, and preparing it for better adherence and colonization of metastatic cells. Wang
et al., recently showed that miR181-5p might be transferred by cancer-associated fibroblast exosomes to breast cancer
cells, inhibiting CDX2, and accelerating EMT [25]. Previous studies by Hoshino et al.,
demonstrated that exosomes could establish at future metastatic locations, and the
location of this could be determined in part owing to the combination of integrins
situated on the exosomes [54]. Remarkably, a recent study from Yuan et al., suggested
that bone metastases were more closely associated with breast cancer exosomes
harboring miR-21 than non-metastatic tumors [55]. Moreover, exosomes can carry
enzymes that facilitate the degradation of the extracellular matrix, allowing cancer
cells to invade surrounding tissues and intravasate into blood or lymphatic vessels,
ultimately spreading to distant organs [56]. By modifying the tumor microenvironment and enhancing the migratory and invasive abilities of cancer cells, exosomes
contribute significantly to cancer progression [57].
Recent research on breast cancer exosomes containing miR-4443, which blocks tissue inhibitors of metalloproteinase 2 (TIMP2), suggested that the tumoral ECM may
be degraded [58]. This study employed a mouse model to demonstrate that the release
of these exosomes promoted metastasis and reduced metastases in vivo as a consequence of miR-4443 suppression [58]. Exosomes can carry different biomolecules,
such as RNA, miRNA, DNA, and proteins, or which can influence different signaling
pathways in other cells, according to numerous recent studies [59]. These may involve
transfers between cancer cells and stromal cells or autocrine/paracrine actions on
cancer cells [6]. A recent study demonstrated that lymph angiogenesis and enhanced
metastasis through lymph nodes were induced by exosomes produced by bladder
cells that contained the lncRNA LNMAT2 [60]. Another study revealed that EphA2,
a kinase that influences ERK signaling to accelerate cancer growth, was abundant in
exosomes isolated from drug-resistant breast cancer cells [60]. Exosomal SOX2 DNA
was examined as a potential biomarker of glioblastoma cancer progression [61].
. Exosomes as mediators of drug resistance in cancer
Drug resistance is a critical issue in the field of medicine, affecting the effectiveness
of various treatments [62]. One emerging area of research that holds great promise
Exosome-Based Smart Drug Delivery for Cancer Treatment
DOI: http://ITexLi.113744
Figure 2.
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Exosome mediated chemo-resistance.
in tackling drug resistance [63]. Exosomes have recently emerged as key mediators in the development and propagation of drug resistance in cancer and other
diseases [64, 65]. Drug resistance is a complex phenomenon characterized by cells
becoming less responsive or resistant to the effects of therapeutic drugs (Figure )
[66]. This can occur through various mechanisms, including reduced drug uptake,
increased drug efflux, altered drug metabolism, and the activation of cell survival
pathways [66]. One-way exosomes contribute to drug resistance by transporting
molecules involved in the resistance phenotype. For instance, exosomes secreted
by cancer cells can carry multidrug resistance proteins, such as P-glycoprotein,
which actively pump chemotherapeutic drugs out of recipient cells, reducing their
efficacy [67].
Additionally, exosomes may transfer genetic material, such as microRNAs and
circular RNAs, that can alter cellular signaling pathways, leading to drug resistance
[68]. Interestingly, exosomes themselves can be influenced by the presence of
drugs, further affecting drug resistance. Studies have shown that chemotherapeutic
drugs can modify the cargo composition of exosomes, making them more resistant
to treatment [69]. This implies that exosomes contribute not only to drug resistance
but also adapt to therapy, potentially amplifying resistance mechanisms. Examples
of the second approach indicated above have been demonstrated in a variety of
cancers. For example, breast cancer cells may directly sequester adriamycin in
exosomes to increase resistance [70]. By using UV spectrophotometry, it was
demonstrated that adriamycin was localized within the exosomes secreted by drugresistant cells [70].
. Exosomes as key players in angiogenesis
Several mechanisms have been proposed to explain how exosomes promote
angiogenesis [71]. One mechanism involves the direct transfer of pro-angiogenic
molecules from exosomes to recipient cells [72]. Exosomes have emerged as critical
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Figure 3.
Role of exosome in angiogenesis.
players in tumor angiogenesis [72–75]. For example, exosomal transfer of vascular
endothelial growth factor (VEGF), fibroblast growth factor (FGF), and matrix metalloproteinases (MMPs) can activate endothelial cells, promoting their sprouting and
migration towards the site of angiogenesis [71]. Additionally, cancer cell-derived
exosomes can influence the behavior of stromal cells in the tumor microenvironment, further enhancing angiogenesis and supporting tumor growth [76]. Moreover,
exosomes can mediate angiogenesis by altering the expression of specific genes or
proteins in recipient cells. Figure illustrates these effects.
Exosomal cargo, such as microRNAs, can be transferred to endothelial cells and
regulate gene expression, thereby modulating angiogenic processes [77]. The transfer
of functional microRNAs, which can act as regulators of gene expression, provides an
additional layer of complexity to the exosome-mediated regulation of angiogenesis.
Understanding the mechanisms by which exosomes promote angiogenesis provides
exciting opportunities for developing novel therapeutic strategies aimed at modulating angiogenesis in diverse contexts, ranging from tissue regeneration to cancer
treatment. Further research in this field holds the potential to revolutionize the field
of vascular biology and improve patient outcomes in a variety of diseases.
. Emerging role of exosomal lncRNAs in tumor progression and metastasis
Exosomal long non-coding RNAs (lncRNAs) are important components of the
tumor microenvironment [78, 79]. They have been reported to modify a variety
of characteristics of the tumor microenvironment in the setting of cancer, including immune evasion, tumor development, angiogenesis, metastasis, and drug
resistance [80]. Additionally, lncRNAs have the potential to be used as diagnostic
or prognostic biomarkers in several cancer types [81], and can be extracted from a
variety of biofluids, including urine, blood, and saliva offering a non-invasive way
to track the progression of diseases. Studies have confirmed that exosomal lncRNAs
exhibit differential expression in cancer patients as compared to healthy individuals,
Exosome-Based Smart Drug Delivery for Cancer Treatment
DOI: http://ITexLi.113744
suggesting their potential as non-invasive diagnostic tools. Clinicians may be able
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to identify malignancies at an early stage by evaluating the expression of exosomal
lncRNAs, enabling prompt treatment options and improving patient outcomes. One
study revealed that PCAT-1, MALAT1, and SPRY4-IT1 were substantially concentrated in urine samples [82], while pCAT-1 and UbC H19 were elevated in the serum
of bladder cancer patients [83, 84].
Patients with prostate cancer had elevated levels of P21 in their urine [85].
Numerous elevated lncRNAs have been identified through plasma analysis as potential biomarkers for various malignancies, including SAP30L-AS1 and SChLAP1 for
prostate cancer [79], HOTAIR for breast cancer, the LNCV6 family for colon cancer,
SOX2-OT for lung squamous cell carcinoma, and the LNCV6 family for colorectal
cancer. Within the cervicovaginal lavage of cervical cancer patients, HOTAIR and
MALAT1 were elevated while MEG3 was downregulated [86]. Upregulation of
MALAT1 was seen in serum biomarker analysis for epithelial ovarian cancer [87],
UEGC1 and HotTip for gastric cancer [88–90] HOTAIR for glioblastoma multiforme
[90]. On the other hand, certain exosomal lncRNAs have been found to have tumorsuppressive effects, inhibiting tumor cell proliferation and metastasis. For instance,
lncRNA Gas5 has been identified to be downregulated in non-small cell lung cancer
patients’ serum, pointing to its potential function as a tumor suppressor [91]. In a
previously described CRC animal model, carcinoma-associated fibroblasts (CAFs)
were found to enhance stemness and chemoresistance by transferring exosomal H19
lncRNA, which in turn activated the beta-catenin pathway [92]. It has been demonstrated that the lncRNA RUNX2-AS1 contained in multiple myeloma exosomes
interacts with the transcription factor RUNX2 to reduce the osteogenic potential of
mesenchymal stem cells [93]. Under hypoxic conditions, the lncRNA UCA1 found in
the exosomes of bladder cancer cells facilitated EMT and altered the tumor microenvironment [94].
The pro-oncogenic CCAT2, POU3F3, and HOTAIR in glioma cells, as well as
exosomal lncRNAs, have been demonstrated to enhance angiogenic factors and
hence promote invasion and metastasis [95–97]. Apoptosis suppression was indicated by an increase in Bcl2 expression and a decrease in Bax and caspase 3 [98]. The
lncRNA MALAT1, which is derived from exosomes of epithelial ovarian cancer cells,
has been identified to promote the pro-angiogenic genes VEGF-A, VEGF-D, IL-8,
and angiogenin [87]. Another Study demonstrated that PCAT1 binds to miR-326 to
enhance cell proliferation in esophageal squamous cell carcinoma while MALAT1
stimulates cell proliferation in breast cancer and non-small cell lung cancer
[99,100]. ZFAS1 stimulates cell cycle, apoptosis, and EMT in gastric cancer [59],
whereas UCA1 has the same impact in bladder cancer [94]. By altering the expression of HNRNPK, 91H promotes metastasis in colorectal cancer [101]. H19 competes
with miR-141 and turns on the β-catenin pathway, retaining tumor cell stemness
and driving drug resistance [92]. RUNX2-AS1, LncRNA H19, FMR1-AS1, and Sox2ot
have been examined for their functions in promoting tumor stem cells in various
malignancies [92, 93, 102, 103].
Exosomal lncRNA has also been found to be a significant contributor to drug
resistance in several malignancies. For example, UCA1 was the cause of tamoxifen
resistance in breast cancer [104], cisplatin resistance in ovarian cancer [105], and
cetuximab resistance in metastatic colorectal cancer [106]. For instance, AGAP2-AS1
and SNHG14 have reported trastuzumab resistance in breast cancer [91, 107].
Gefitinib resistance in esophageal squamous cell carcinoma was caused by Part1
[108]. Increased lncRNA SBF2-AS1 activity in glioblastoma has been related to
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temozolomide resistance [68]. Erlotinib and gefitinib resistance in non-small cell
lung cancer has been associated with RP11-838N2.4 and H19 [98, 109]. Sunitinib
resistance was increased by ARSR in renal cancer [110]. Moreover, exosomal lncRNAs
can also modulate the tumor immune response. They can influence the activity and
function of various immune cells, such as T cells, natural killer cells, macrophages,
and dendritic cells [111]. By regulating immune cell functions, exosomal lncRNAs
can impact immune surveillance, immune evasion, and immune suppression within
the tumor microenvironment. In a nutshell, exosomal lncRNAs have emerged as
important regulators of the tumor microenvironment. Their expression patterns
have been linked to tumor aggressiveness, metastasis, and drug resistance. Therefore,
exosomal lncRNAs may serve as prognostic indicators and therapeutic targets.
Modulating the expression or function of exosomal lncRNAs could potentially
interfere with tumor growth, reduce metastatic potential, and sensitize cancer cells to
existing therapies.
. Promising role of exosomes in enhancing drug delivery to specific
cellular targets
Exosomes are being extensively explored for targeted delivery in cancer treatment.
They offer several advantages in this context. One of the key benefits is their ability to
specifically target cancer cells, reducing off-target effects and enhancing the effectiveness of therapy. Researchers have been able to modify the surface of exosomes
to ensure their uptake by cancer cells. By loading these engineered exosomes with
therapeutic agents such as drugs, siRNAs, or gene-editing tools, they can deliver the
cargo directly to the tumor site. This targeted delivery enables the potent anticancer
agents to act specifically on cancer cells, increasing their efficacy while minimizing
adverse effects on healthy tissues. This was demonstrated by employing the delivery
of siRNA to bladder cancer cells using exosomes that were obtained from HEK293
human embryonic kidney cells. Electroporation was used to introduce PLK1 siRNA to
the exosomes before they were co-cultured with UMUC3 metastatic bladder cancer
cells. According to an in vitro study, bladder cancer cells internalized HEK293 exo-
somes more than normal bladder cells, which resulted in an efficient knockdown of
PLK-1 mRNA and protein [21].
Exosomes can also carry drugs that are otherwise challenging to deliver directly
to tumor tissues. These vesicles have the advantage of being able to navigate through
biological barriers, including the extracellular matrix and the blood-brain barrier, to
reach their intended target. This ability makes them particularly useful for delivering therapeutics to tumors located in difficult-to-reach sites [112, 113]. A zebrafish
model was used to examine the exosomes in vivo after they had been extracted,
characterized, and loaded with chemo agents via incubation. In comparison to
the basic drugs, the loaded exosome systems demonstrated substantially better
CNS delivery capability [114]. Moreover, exosome-mediated chemotherapeutic
administration has been found to increase anti-cancer effects in a number of studies
[115–118]. Doxorubicin, another of the most potent anti-cancer drug, is employed
to treat leukemia, lymphoma, and a variety of solid tumors. It has been observed
that exosomes can carry chemotherapeutic drugs like doxorubicin and paclitaxel.
However, because of its poor biocompatibility and substantial side effects such
as bone marrow suppression and cardiotoxicity, the clinical usage of doxorubicin
Exosome-Based Smart Drug Delivery for Cancer Treatment
DOI: http://ITexLi.113744
is extremely limited. Many nanoparticle technologies are being used to improve
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doxorubicin’s biocompatibility and anti-cancer properties, but they also cause
immunological response and oxidative damage [118, 119]. Exosome-mediated anticancer therapy has extensively investigated doxorubicin because of its easy-to-track
intrinsic fluorescence [118]. The optimized cholesterol endocytosis process and
phospholipid composition of exosomal membranes allow exosomes to target cancer
cells better than liposomes [120]. Since doxorubicin frequently causes cardiotoxicity, loading doxorubicin into exosomes prevents doxorubicin from reaching cardiac
endothelial cells. As a result, this lowers the risk of cardiotoxicity [121]. It has
been revealed more recently that the cellular absorption rate and anticancer effect
of doxorubicin in osteosarcoma could be improved by exosomes produced from
mesenchymal stem cells [122]. In cisplatin-resistant patients, paclitaxel is frequently
used to overcome drug resistance [123]. Mesenchymal stromal cells treated with
paclitaxel were able to generate paclitaxel-loaded exosomes, which exhibited powerful anti-cancer effects in human pancreatic cancer [26]. MDR stands for multiple
drug resistance, and it is one of the main challenges to effective cancer treatment.
Exosomes have demonstrated efficacy in overcoming multidrug resistance in cancers. In MDCK MDR1 cells, paclitaxel-loaded macrophage-derived exosomes demonstrated higher cell uptake and a lower IC50 than free paclitaxel, circumventing
the P-glycoprotein drug efflux transporter [30]. Exosomes produced from U-87 MG
cells have the potential to deliver paclitaxel and overcome MDR, which could lead
to an enhanced therapeutic effect in glioblastoma multiforme [124]. Furthermore,
the use of exosomes in cancer treatment holds promise for personalized medicine.
Exosomes can be isolated from a patient’s own cells, loaded with specific therapeutic
agents, and then reintroduced back into the patient. This approach takes advantage
of the unique characteristics of each patient’s tumor, tailoring the treatment to their
specific needs. While the use of exosomes in targeted delivery for cancer treatment
shows great potential, there are still challenges that need to be addressed. These
include optimizing exosome production and cargo loading techniques, ensuring
the stability of exosomes during storage and transportation, and further improving
their targeting efficiency. In addition, the exosomes were native to the animal and
were small, so they naturally avoided phagocytosis, which lowered the immunological response [125]. Zhou et
mesenchymal stem cells were loaded with siRNA and oxaliplatin and used for the
treatment of pancreatic cancer in a rat model. In
increased the uptake of these compounds, indicating a greater therapeutic effect
than a free drug.
Exosomes have also been explored as potential diagnostic and prognostic biomark
ers in cancer. The analysis of exosomes obtained from body fluids, such as blood or
urine, can provide valuable information about the presence of specific genetic alterations or the expression of tumor-related molecules. This non-invasive approach has
the potential to revolutionize cancer diagnosis and monitoring, allowing for earlier
detection and personalized treatment strategies. Qambrani et
that cancer-cell-derived exosomes can function as both a drug delivery system and
a potential fluorescent biomarker, as shown by HeLa-derived exosomes loaded with
doxorubicin and silver nanoclusters [127]. Recently, there has been growing interest
in using exosomes derived from bovine milk as a drug delivery vehicle [128, 129].
For example, Li et
therapeutic impact against cancer cells in
[130] recently demonstrated that doxorubicin uptake and
al.,
[126] showed that exosomes from bone marrow
al.,
vitro
vivo
and in
were considerably improved by first
vitro
, exosomal delivery
[127] demonstrated
al.,
-
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isolating milk exosomes, coating them with hyaluronan for CD44-targeting, and then
loading them with the drug. Figure depicts the appearance of an isolated exosome
and exosome-specific biomarker analysis in the experimental context [131].
In a recent study, Carobolante et al., delineated that milk-derived exosomes had a
less efficient uptake when compared to exosomes produced by Caco-2 epithelial cells.
Additional modifications are necessary for milk-derived exosomes to be utilized as a
drug delivery system [132]. Another study confirmed that paclitaxel-loaded exosomes
(milk derived) inhibited tumor growth more effectively than free paclitaxel, with
fewer systemic side effects [133]. In one instance of drug delivery, exosomes containing curcumin were used to treat inflammatory disease. In a clinical trial, exosomes
formed a complex with curcumin that increased its effectiveness compared to free
curcumin. In another study, curcumin was loaded onto exosomes derived from EL-4
murine tumor cells via incubation.
In vitro experiments revealed that exosomal
curcumin substantially decreased inflammatory cytokine levels when compared to
curcumin in its native form [134–136].
Exosomes have been extensively studied for their ability to deliver genetic therapies including small interfering RNA (siRNA) and microRNA (miRNA), because
they naturally carry nucleic acids like DNA and RNA [3, 5], as previously mentioned
[117]. The expression levels of target genes can be downregulated or disrupted using
siRNA as a therapeutic agent. Typically, siRNA is unstable and rapidly destroys in the
Figure 4.
(A) A flowchart depicting the isolation of exosomes from human peripheral blood neutrophils (N-ex). (B)
Transamination electron microscopy (TEM) analysis of N-ex. (C and D). Morphological study of N-ex using
atom force microscopy (AFM). N-ex nanoparticle tracking assay (NTA) for size determination particle size
(E), zeta potential (F). (G) DLS was used to measure the PDI of N-ex. (H) Western blot studies of exosomal
biomarkers (CD63, CD81 CD9, and Alix) and ER markers (calnexin) in N-ex. (I and J) fluorescence confocal
laser microscopy and imaging flow cytometry were used to investigate DiR-labeled N-ex untacking in the gastric
cancer cell (HGC27). The nuclei of the cells were stained with nuclear dye DAPI. Scale bars, 20μm. Adopted
from ref. [131].
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bloodstream. Exosomes serve as a delivery vehicle for these RNA molecules, protect-
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al.,
ing them from destruction in systemic circulation [117]. Kamerkar et
siRNA-loaded exosomes in pancreatic cancer mice models [137]. This study proves
that compared to siRNA-loaded liposomes; the exosome group showed a higher
reduction in tumor growth as well as a lower clearance from the body. Wahlgren
et
[32] reported that exogenous siRNA was inserted into exosomes delivered to
al.,
human blood cells after exosomes were isolated from lung cancer cells, suggesting the
potential of utilizing exosomes for gene therapy. Nevertheless, the advancements in
exosome research provide a promising avenue for improving cancer treatment outcomes and minimizing side effects associated with conventional therapies. Ongoing
studies continue to explore the full potential of exosomes in targeted delivery for
cancer therapy.
. Challenges and limitations in implementing exosome-based therapies
used kRAS
in clinical practices
Exosomes have gained significant attention in the field of medicine due to their
potential clinical applications. One of the most promising applications of exosomes
is in regenerative medicine. Exosomes derived from stem cells have shown great
potential in promoting tissue repair and regeneration. They can transfer bioactive
molecules such as proteins, nucleic acids, and lipids to target cells, stimulating healing
processes. As previously discussed, exosomes, could deliver drugs to target areas and
cross barriers when compared to other nanoparticles. Exosomes’ drug efficacy and
half-life were well maintained when they were injected into the recipient cell, according to the research findings. Because the exosomes are endogenous mediators, they
possess natural cell permeability, which allows them to pass physical barriers and even
avoid lysosomal breakdown and endosomal pathways [138]. Macrophage-derived
genetically engineered exosomes can transport drugs without being rejected [139].
These targeting characteristics can be tailored to malignancies or other disorders with
specific markers or proteins. They can also cross the BBB, allowing CNS-active drugs
to be delivered [125].
Exosomes also hold promise as diagnostic markers for several cancer types and as
an early detection tool in many clinical studies. This has the potential to revolutionize disease diagnosis and monitoring, enabling earlier detection and personalized
treatment approaches. For instance, the goal of the colon cancer clinical study
NCT04523389 is to create diagnostic markers. As seen on Clinicaltrials.gov, accessed
on Aug 8, 2023, there are currently dozens of trials when searching for the terms “cancer” and “exosomes.” While most focus on the use of exosomes as a diagnostic marker,
some have a specific interest in using exosomes as a delivery system. However, despite
the progress made in exosome research, several challenges remain. Standardization
of methods for exosome isolation, characterization, and quantification is crucial for
ensuring consistent and reliable results. Additionally, the large-scale production of
exosomes and their scalable purification for clinical use need to be addressed [125].
Overall, the clinical use of exosomes is an exciting and rapidly evolving field. With
further research and development, exosomes hold immense promise for advancing
regenerative medicine, diagnostics, and drug delivery, potentially transforming the
way we approach various diseases and conditions in the future. Table
recent clinical trials demonstrating the various ways to exploit exosomes as a natural
drug delivery system.
highlights
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