The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System

In the paper

“Following in-depth investigations revealed that exosomes could be released by tumor cells, immune cells, mesenchymal stem cells, and endothelial progenitor cells and are widely detectable in blood, cerebrospinal fluid, saliva, ascites, and even urine [3].”

What the sources say

• Partly supported

  The Background (page unavailable) says that tumour cells and several immune-cell types release exosomes, and that exosomes occur in plasma, saliva, urine, and malignant effusions. It does not identify mesenchymal stem cells or endothelial progenitor cells as producers, or cerebrospinal fluid as a location; it also does not specifically name ascites, though malignant effusions may include it. (LLM, conf=0.88)

  cites [3] Alikhani, 2011, Human saliva, plasma and breast milk exosomes contain RNA: Uptake by macrophages, J. Transl. Med. sourceExperimental — accuracy not yet measured

In the paper

“Moreover, exosomes widely participate in biological activities such as cell communication, migration, angiogenesis, immunomodulation, and proliferation.”

In the paper

“Parts of MVBs could be fused to lysosomes, and their contents are degraded or recycled.”

In the paper

“In addition, exosomes are regulated by cytokines growth factors, proteins, distinct cell types, and other physicochemical conditions at multiple stages in the production process and widely exist in cells and body fluids in vivo, making them well-tolerated and -regulated [17].”

What the sources say

• Not checked yetcites [17] Meldolesi, 2018, Exosomes and Ectosomes in Intercellular Communication, Curr. Biol. source

In the paper

“Those unique tissue- or cell-specific proteins and genetic materials help to identify their cellular origin and the status of parental cells.”

In the paper

“Even plant-derived exosomes have been characterized and shown to have structures similar to mammalian exosomes to mediate plant–animal intercellular communication [5].”

What the sources say

• Not checked yetcites [5] Zhang, 2016, Plant derived edible nanoparticles as a new therapeutic approach against diseases, Tissue Barriers source

In the paper

“Now, it is generally accepted that exosomes are 30–100 nm in diameter, rich in lipids (cholesterol, sphingomyelin, and ceramide), and fulfilled with active molecules including DNA, noncoding RNA, mRNA or protein (Table 1) [4].”

What the sources say

• Not checked yetcites [4] Kowal, 2014, Biogenesis and secretion of exosomes, Curr. Opin. Cell Biol. source

In the paper

“Studies have shown that ESCRT-0, ESCRT-I, and ESCRT-II may be regulating cargo sorting, and ESCRT-III is involved in membrane endocytosis and exocytosis.”

What the sources say

• Not checked yetcites [13] 2020, A Structural View on ESCRT-Mediated Abscission, Front. Cell Dev. Biol. source
• Not checked yetcites [14] Zhen, 2020, ESCRT-mediated phagophore sealing during mitophagy, Autophagy source

In the paper

“Exosomes are mainly formed by endocytosis of cell membranes, followed by converting to multivesicular bodies (MVBs) with dynamic subcellular architecture.”

In the paper

“As an emerging drug delivery carrier, exosomes loaded with chemical or genetic drugs play a promising therapeutic role in diseases.”

In the paper

“Exosomes are biphospholipid bodies formed from membranes and emitted by cells [1].”

What the sources say

• Not checked yetcites [1] Boyiadzis, 2015, Information transfer by exosomes: A new frontier in hematologic malignancies, Blood Rev. source

In the paper

“In addition, Vps4 and ALIX also participate in cargo sorting and exosome formation [15,16].”

What the sources say

• Not checked yetcites [15] Jackson, 2017, Effects of Inhibiting VPS4 Support a General Role for ESCRTs in Extracellular Vesicle Biogenesis, Biophys. J. source
• Not checked yetcites [16] Larios, J., Mercier, V., Roux, A., and Gruenberg, J. (2020). ALIX- and ESCRT-III–dependent sorting of tetraspanins to exosomes. J. Cell Biol., 219. source

In the paper

“The biogenesis mechanism of exosomes is controlled by related proteins, including annexin and tetraspanins (CD63).”

In the paper

“Therefore, exosomes as naturally derived biological carriers have been refined into the concept of drug delivery.”

In the paper

“Exosomes could be detected in almost any body fluids (blood, cerebrospinal fluid, saliva, etc.), indicating their transport cargo could go through membrane and be protected from degradations [30].”

What the sources say

• Not checked yetcites [30] Lai, 2013, Exosomes for drug delivery—A novel application for the mesenchymal stem cell, Biotechnol. Adv. source

In the paper

“After intramyocardial injection, they found that CMP-targeted CDC-derived exosomes could help in increasing cardiomyocyte uptake, decreasing apoptosis, and promoting cardiac retention.”

What the sources say

• Not checked yetcites [25] Mentkowski, 2019, Exosomes Engineered to Express a Cardiomyocyte Binding Peptide Demonstrate Improved Cardiac Retention in Vivo, Sci. Rep. source

In the paper

“However, these materials have the following disadvantages: low transduction efficiency, lack of target specificity, rapid degradation, and toxicity.”

In the paper

“A plentiful number of proteins and genetic molecules as a component in exosomes indicate that the great majority of biological substances can be loaded without unexpected interactions with the carrier.”

What the sources say

• Not checked yetcites [28] Wei, 2021, Regulation of exosome production and cargo sorting, Int. J. Biol. Sci. source

In the paper

“They have superior compatibility that is critical to their function as carriers [28], which also shows a tremendous inherent capacity for receiver cells [29].”

What the sources say

• Not checked yetcites [28] Wei, 2021, Regulation of exosome production and cargo sorting, Int. J. Biol. Sci. source
• Not checked yetcites [29] Anand, 2019, Ticket to a bubble ride: Cargo sorting into exosomes and extracellular vesicles, Biochim. Biophys. Acta Proteins Proteom. source

In the paper

“Their result showed that AA-modified vesicles had a better loading capacity and therapeutic efficiency in vivo [26].”

What the sources say

• Not checked yetcites [26] Kim, 2018, Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: In vitro and in vivo evaluations, Nanomedicine source

In the paper

“Furthermore, the protein corona causes an immune response and is quickly cleared from the blood (Figure 2) [36,37].”

What the sources say

• Not checked yetcites [36] Xiao, 2021, The protein corona hampers the transcytosis of transferrin-modified nanoparticles through blood-brain barrier and attenuates their targeting ability to brain tumor, Biomaterials source
• Not checked yetcites [37] Sutaria, 2017, Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading, Pharm. Res. source

In the paper

“For instance, exosomes can cross the blood–brain barrier (BBB) and transport specific drugs to the neural cell [39], significantly retaining side effects including toxicity.”

What the sources say

• Not checked yetcites [39] Zhang, 2015, Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury, J. Neurosurg. source

In the paper

“Unlike synthetic liposomes, exosomes can be loaded with cargo in vivo by transfection and in vitro by electroporation and lipofection [33].”

What the sources say

• Not checked yetcites [33] Xi, 2021, Drug loading techniques for exosome-based drug delivery systems, J. Pharm. Sci.

In the paper

“With the above advantages, exosomes are capable to refrain from phagocytosis and cross biological barriers with therapeutic substances (proteins, mRNAs, lipids, chemical drugs) to sites that are difficult to arrive at by artificial carriers.”

In the paper

“Therefore, exosomes have good biocompatibility as carriers, which can prolong the circulation half-time with therapeutic cargo [38].”

What the sources say

• Not checked yetcites [38] Fernandes, 2020, Exosome-like Nanoparticles: A New Type of Nanocarrier, Curr. Med. Chem. source

In the paper

“Notably, DC-derived exosomes gain MHC-I that combines with tumor-derived peptides, and the complex could activate NK or T cells to suppress tumors [45,46].”

What the sources say

• Not checked yetcites [45] Hartman, 2011, Increasing vaccine potency through exosome antigen targeting, Vaccine source
• Not checked yetcites [46] Romagnoli, 2015, Dendritic Cell-Derived Exosomes may be a Tool for Cancer Immunotherapy by Converting Tumor Cells into Immunogenic Targets., Front. Immunol. source

In the paper

“With the promising and highly efficient carry potentials in DDS, exosomes are showing good biocompatibility, non-immunogenicity, and biodegradability and intensively investigated in the therapeutic role for different diseases.”

In the paper

“Furthermore, strong immunogenic proteins embedded in exosomes may provoke immune activation to inhibit cancer proliferation with the potential for developing cancer vaccines.”

In the paper

“Exosomes rich in genetic material, proteins, and lipids may carry effective communication information for donor cells and target cells, which may build up the tumor microenvironment (TME) [40].”

What the sources say

• Not checked yetcites [40] Li, 2019, Exosomes in the tumor microenvironment as mediators of cancer therapy resistance, Mol. Cancer source

In the paper

“Furthermore, exosome transport solves the problem of easy degradation of miRNAs in vivo, implying a new tumor therapy [50].”

What the sources say

• Not checked yetcites [50] Ell, 2013, Tumor-Induced Osteoclast miRNA Changes as Regulators and Biomarkers of Osteolytic Bone Metastasis, Cancer Cell source

In the paper

“Therefore, TDEs could be devised as natural drug carriers with higher cancer cell targeting and therapeutic efficacy, low toxicity, and permeability [41].”

What the sources say

• Not checked yetcites [41] Tarasov, 2021, Extracellular vesicles in cancer nanomedicine. Semin, Cancer Biol. source

In the paper

“In pancreatic cancer, it was shown that exosomes loaded with the survival protein-T34A protein induced apoptosis and enhanced the gemcitabine-killing effect [43].”

What the sources say

• Not checked yetcites [43] Aspe, 2014, Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant, J. Extracell. Vesicles source

In the paper

“Tang et al. showed another example that exosomes pre-loaded with cisplatin could significantly decrease liver or kidney toxicities and suppress tumors in ovarian cancer mice xenograft model [58].”

What the sources say

• Not checked yetcites [58] Tang, 2012, Delivery of chemotherapeutic drugs in tumour cell-derived microparticles, Nat. Commun. source

In the paper

“For example, Saari et al. showed that tumor cell-derived exosomes could be considered a useful vehicle for paclitaxel from the parental cell, carrying the drug into recipient cells through the endocytosis pathway and increasing their cytotoxicity [56].”

What the sources say

• Not checked yetcites [56] Saari, 2015, Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells, J. Control. Release source

In the paper

“Antitumor drugs such as vincristine, curcumin, PTX, camptothecin, etc., most of which are monomer active ingredients extracted from Chinese medicine, generally have disadvantages including poor stability, low solubility, high hydrophobicity, and short half-life, etc. Therefore, their low bioavailability limited the clinical application.”

In the paper

“In addition, this system exhibits remarkable cell absorption and cytotoxicity in tumor cells [61].”

What the sources say

• Not checked yetcites [61] Yong, 2019, Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy, Nat. Commun. source

In the paper

“Brien et al. reported that mesenchymal stem cells (MSC)-derived exosomes containing miR-379 were shown to have a therapeutic effect on breast cancer, with significantly reduced tumor growth rates in T47D breast cell line expressing miR-379 [51].”

What the sources say

• Not checked yetcites [51] Khan, 2018, Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379, Oncogene source

In the paper

“Therefore, exosome carriers possess superior biocompatibility, causing drugs more easily uptake by the cells and avoiding drug resistance (Figure 3).”

In the paper

“The researchers loaded Nefmut into exosomes and fused a single-chain fragment variable antibody at its C-terminus to form engineered exosomes, which proposed a novel targeted strategy for endogenous engineering in the treatment of neurodegenerative diseases based on exosomes released by the cellular composition of the CNS [73].”

What the sources say

• Not checked yetcites [73] Ferrantelli, F., Chiozzini, C., Leone, P., Manfredi, F., and Federico, M. (2020). Engineered Extracellular Vesicles/Exosomes as a New Tool against Neurodegenerative Diseases. Pharmaceutics, 12. source

In the paper

“Notably, exosomes specifically delivered loaded cargo to neurons in the brain, downregulating the siRNA target gene and impacted on Alzheimer’s disease (AD) [70].”

What the sources say

• Not checked yetcites [70] Seow, 2011, Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes, Nat. Biotechnol. source

In the paper

“In the central nervous system (CNS), exosomes have a role in mediating intercellular communication, maintaining homeostasis, and neuroprotective (Table 2).”

In the paper

“In summary, TDEs contain tumor-associated antigens that can preferably identify tumors and targeted transmit therapeutic substances.”

In the paper

“Their findings demonstrated that the engineered exosome strongly improved the treatment of glioma while reducing side effects [62].”

What the sources say

• Not checked yetcites [62] Jia, 2018, NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo, Biomaterials source

In the paper

“To suppress the side effects of methotrexate, researchers encapsulated the chemical drug in exosomes from MSCs, and it showed better retention and a 10-fold inhibition of inflammation compared to methotrexate alone [80].”

What the sources say

• Not checked yetcites [80] Neupane, 2020, Biocompatible Nanovesicular Drug Delivery Systems with Targeting Potential for Autoimmune Diseases, Curr. Pharm. Des. source

In the paper

“Similarly, Kadry et al. found the glutathione-loaded exosomes were more able to shorten the glutathione synthesis process, increase glutathione serum levels, and meanwhile reduce rheumatoid factors.”

What the sources say

• Not checked yetcites [81] Kadry, 2019, Liposomal glutathione as a promising candidate for immunological rheumatoid arthritis therapy, Heliyon source

In the paper

“After applying the above exosomes, the experimental autoimmune encephalomyelitis score decreased sharply, significantly reducing tissue damage.”

What the sources say

• Not checked yetcites [83] Casella, 2018, Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis, Mol. Ther. source

In the paper

“In vivo biodistribution experiments showed that these engineered exosomes better protected bone and cartilage in CIA mice and reduced joint inflammation without obvious liver toxicity.”

What the sources say

• Not checked yetcites [82] Yan, 2020, Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis, J. Nanobiotechnol. source

In the paper

“The researchers found significantly higher efficiency after conjugating the STExo surface with BMSC-specific aptamers, confirming the novel modification could help in osteoporosis and fractures [87].”

What the sources say

• Not checked yetcites [87] Luo, 2019, Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration, Nanoscale source

In the paper

“For example, injecting miR-19a-3p-loaded exosomes into mouse myocardium revealed that exosomes resulted in improved angiogenesis, decreased myocardial fibrosis, and increased left ventricular ejection fraction [92].”

What the sources say

• Not checked yetcites [92] Graber, 2010, miR-19a-3p containing exosomes improve function of ischaemic myocardium upon shock wave therapy, Cardiovasc. Res.

In the paper

“Another study showed that targeting Kartogenin (KGN) to synovial fluid-derived mesenchymal stem cells (SF-MSCs) by engineered exosomes resulted in uniform dispersion of KGN in the cytoplasmic matrix, increased concentration in the target, and significantly promoted chondrogenesis of SF-MSCs.”

What the sources say

• Not checked yetcites [89] Xu, 2021, Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration, Biomaterials source

In the paper

“Moreover, the treatment of the engineered bone scaffolds with exosomes as carriers not only provides direct bracing for bone defects but also provides a suitable status for bone regeneration.”

In the paper

“Similarly, Zhang et al. found that exosomes from adipose tissue-derived stem cells can accelerate collagen synthesis and redeposition through regulating PI3K/Akt pathway. This function helps in full-thickness skin wounds, ultimately reducing healing time and scarring in mouse models [103].”

What the sources say

• Not checked yetcites [103] Zhang, 2018, Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway, Exp. Cell Res. source

In the paper

“For example, exosomes derived from human umbilical vein endothelial cells (HUVECs) can promote collagen maturation and angiogenesis and regulate the keratinocytes and fibroblast growth, thereby accelerating skin wound healing [102].”

What the sources say

• Not checked yetcites [102] Zhao, 2020, GelMA combined with sustained release of HUVECs derived exosomes for promoting cutaneous wound healing and facilitating skin regeneration, Histochem. J. source

In the paper

“Compared with M1-Exo and GEM, M1-Exo-GEM had significantly up-regulated the expression of inflammatory cytokines and stronger cytotoxic effect on cancer cells [100].”

What the sources say

• Not checked yetcites [100] Tang, 2022, M1 macrophage-derived exosomes synergistically enhance the anti- bladder cancer effect of gemcitabine, Aging source

In the paper

“Further reports showed the Mel@NVs could promote the formation of microvessels and alleviate cardiac fibrosis, thereby further restoring mitochondrial dysfunction for myocardial repair.”

What the sources say

• Not checked yetcites [96] Zhang, 2022, Melatonin Engineered Adipose-Derived Biomimetic Nanovesicles Regulate Mitochondrial Functions and Promote Myocardial Repair in Myocardial Infarction, Front. Cardiovasc. Med. source

In the paper

“enable exosomes to deliver substances such as chemical drugs, nucleic acids, and proteins, etc.”

In the paper

“a higher safety profile that escapes from immune detection systems”

In the paper

“Similarly, Zhang et al. showed that exosome microRNAs (such as miR-193a-3p, miR-210-3p, and miR-5100) from hypoxic BMSCs were selectively taken up by lung cancer cells and could activate STAT3 signaling to induce epithelial–mesenchymal transition (EMT) to promote the invasion of lung cancer cells, which has been identified as a new biomarker for lung cancer progression [114].”

What the sources say

• Not checked yetcites [114] Zhang, 2019, Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT, Mol. Cancer source

In the paper

“Xia et al. found that exosome-based miR-125b may accelerate myofibroblast differentiation and transfer to young fibroblast by targeting SIRT7. The results show a promising method for counteracting skin aging [107].”

What the sources say

• Not checked yetcites [107] Xia, 2022, Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing, J. Nanobiotechnol. source

In the paper

“a better-tolerated and longer-circulating half-life, which prolongs the cargo from degradation”

In the paper

“a more easy targeting ability, by which the exosomes’ surface could be artificially modified to increase biological effects as carriers and targeted transport”

In the paper

“Similarly, Wang et al. loaded epidermal stem cell (ESC)-derived exosomes with VH298 (VH-EV), and VH-EV was shown to promote the function of HUVECs in vitro through HIF-1α signaling. This special exosome displayed great therapeutic effects on skin regeneration [106].”

What the sources say

• Not checked yetcites [106] Wang, 2022, VH298-loaded extracellular vesicles released from gelatin methacryloyl hydrogel facilitate diabetic wound healing by HIF-1α-mediated enhancement of angiogenesis, Acta Biomater. source

In the paper

“Exosomes secreted by cells in different tissues carry different biological components”

In the paper

“exosomes are involved in the occurrence and progression of various systemic diseases”

In the paper

“which determine their intrinsic properties of high biocompatibility and low immunogenicity”

In the paper

“methods to regulate cargo packaging and vesicle release in vivo are still limited”