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Cited by 68Extracellular vesicles in diseaseRNA Interference and Gene DeliveryNanoparticle-Based Drug Delivery

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Exosome-mediated delivery of siRNA molecules in cancer therapy: triumphs and challenges

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Ubanako, Philemon, Mirza, Sheefa, Ruff, Paul, Penny, Clement·2024·Frontiers in Molecular Biosciences
DOI 10.3389/fmolb.2024.1447953PMC PMC11442288
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Abstract

The discovery of novel and innovative therapeutic strategies for cancer treatment and management remains a major global challenge. Exosomes are endogenous nanoscale extracellular vesicles that have garnered increasing attention as innovative vehicles for advanced drug delivery and targeted therapy. The attractive physicochemical and biological properties of exosomes, including increased permeability, biocompatibility, extended half-life in circulation, reduced toxicity and immunogenicity, and multiple functionalization strategies, have made them preferred drug delivery vehicles in cancer and other diseases. Small interfering RNAs (siRNAs) are remarkably able to target any known gene: an attribute harnessed to knock down cancer-associated genes as a viable strategy in cancer management. Extensive research on exosome-mediated delivery of siRNAs for targeting diverse types of cancer has yielded promising results for anticancer therapy, with some formulations progressing through clinical trials. This review catalogs recent advances in exosome-mediated siRNA delivery in several types of cancer, including the manifold benefits and minimal drawbacks of such innovative delivery systems. Additionally, we have highlighted the potential of plant-derived exosomes as innovative drug delivery systems for cancer treatment, offering numerous advantages such as biocompatibility, scalability, and reduced toxicity compared to traditional methods. These exosomes, with their unique characteristics and potential for effective siRNA delivery, represent a significant advancement in nanomedicine and cancer therapeutics. Further exploration of their manufacturing processes and biological mechanisms could significantly advance natural medicine and enhance the efficacy of exosome-based therapies.

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Crossref · 10.3389/fmolb.2024.1447953

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FIGURE 1 Exosome biogenesis. (1) The relevant cargoes are internalized by endocytosis. (2) Internalized cargoes are sorted into early endosomes. (3) The early endosomes mature into late endosomes, also known as multivesicular bodies (MVB). Late endosomes/MVBs are specialized endosomal compartments containing intraluminal vesicles (ILVs) that sequester proteins, lipids, cytosolic compartments, and potential exosome cargoes. (4) Cargoes are also delivered from the trans-Golgi network and possibly from the cytosol. (5) Late endosomes containing exosome cargoes get (5) transported to the plasma membrane, (6) fuse with the cell surface and, (7) the ILVs are secreted as exosomes. PM: plasma membrane, ER: endoplasmic reticulum. (Figure used with permission from Gurung et al. (2021)).
FIGURE 1 Exosome biogenesis. (1) The relevant cargoes are internalized by endocytosis. (2) Internalized cargoes are sorted into early endosomes. (3) The early endosomes mature into late endosomes, also known as multivesicular bodies (MVB). Late endosomes/MVBs are specialized endosomal compartments containing intraluminal vesicles (ILVs) that sequester proteins, lipids, cytosolic compartments, and potential exosome cargoes. (4) Cargoes are also delivered from the trans-Golgi network and possibly from the cytosol. (5) Late endosomes containing exosome cargoes get (5) transported to the plasma membrane, (6) fuse with the cell surface and, (7) the ILVs are secreted as exosomes. PM: plasma membrane, ER: endoplasmic reticulum. (Figure used with permission from Gurung et al. (2021)).CC BY · PubMed Central
FIGURE 2 Exosome composition. Exosomes are nano-sized extracellular vesicles produced naturally by all cell types. They contain proteins, nucleic acids, lipids, and metabolites. Exosomes function as intermediaries of intercellular communication and influence different facets of cell biology in disease and normal physiology. (Figure created with Biorender).
FIGURE 2 Exosome composition. Exosomes are nano-sized extracellular vesicles produced naturally by all cell types. They contain proteins, nucleic acids, lipids, and metabolites. Exosomes function as intermediaries of intercellular communication and influence different facets of cell biology in disease and normal physiology. (Figure created with Biorender).CC BY · PubMed Central
FIGURE 3 Multifunctional roles of exosomes in health and disease. Exosomes are nanoscale extracellular vesicles produced by all cells and contain metabolites, proteins, lipids, and nucleic acids, which are pivotal for cell-cell communication. Exosomes mediate near and far intercellular communication in health and disease, influencing different facets of cell biology. Exosome-delivered proteins, metabolites, nucleic acids, and lipids significantly influence the biological response of recipient cells. Such exosome-mediated cellular responses may promote or inhibit the development of diseases such as cancer. Exosomes participate in proliferation, metastasis, immunoregulation, apoptosis, cell differentiation, metabolic reprogramming, cell signaling, gene regulation, and reproduction. (Figure created with Biorender).
FIGURE 3 Multifunctional roles of exosomes in health and disease. Exosomes are nanoscale extracellular vesicles produced by all cells and contain metabolites, proteins, lipids, and nucleic acids, which are pivotal for cell-cell communication. Exosomes mediate near and far intercellular communication in health and disease, influencing different facets of cell biology. Exosome-delivered proteins, metabolites, nucleic acids, and lipids significantly influence the biological response of recipient cells. Such exosome-mediated cellular responses may promote or inhibit the development of diseases such as cancer. Exosomes participate in proliferation, metastasis, immunoregulation, apoptosis, cell differentiation, metabolic reprogramming, cell signaling, gene regulation, and reproduction. (Figure created with Biorender).CC BY · PubMed Central
FIGURE 4 siRNA mechanism of action. The siRNA machinery is an evolutionarily conserved mechanism for the suppression of gene expression. In summary, dicer, a ribonuclease, breaks down long double-stranded RNA, generating short siRNA duplexes (1, 2). siRNAs consist of two overhanging nucleotides and a short 20–24-bp double-stranded RNA (dsRNA) with phosphorylated 5′ and hydroxylated 3′ ends. The siRNA is incorporated into the RNA-induced silencing complex (RISC), where Argonaut 2 protein interacts, degrading the passenger strand (3). The RISC guides the guide strand to the complementary mRNA, causing catalytic cleavage and degradation, ultimately suppressing gene expression (4–6). Synthetic siRNAs can also be transfected into cells to knock down, in principle, any gene of interest with a complementary sequence, thereby validating gene function. (Figure created with Biorender).
FIGURE 4 siRNA mechanism of action. The siRNA machinery is an evolutionarily conserved mechanism for the suppression of gene expression. In summary, dicer, a ribonuclease, breaks down long double-stranded RNA, generating short siRNA duplexes (1, 2). siRNAs consist of two overhanging nucleotides and a short 20–24-bp double-stranded RNA (dsRNA) with phosphorylated 5′ and hydroxylated 3′ ends. The siRNA is incorporated into the RNA-induced silencing complex (RISC), where Argonaut 2 protein interacts, degrading the passenger strand (3). The RISC guides the guide strand to the complementary mRNA, causing catalytic cleavage and degradation, ultimately suppressing gene expression (4–6). Synthetic siRNAs can also be transfected into cells to knock down, in principle, any gene of interest with a complementary sequence, thereby validating gene function. (Figure created with Biorender).CC BY · PubMed Central
FIGURE 5 In vivo delivery of an siRNA-expressing genetic circuit. The genetic circuit is comprised of a VEGFR2 siRNA-expressing backbone and a CMV promoter. Following intravenous administration, the anti-VEGFR2 circuit is transported to the liver. In hepatocytes, the CMV promoter controls the transcription of VEGFR2 siRNA and enables the encapsulation of VEGFR2 siRNA into sEVs. After being released into the blood circulation, VEGFR2 siRNA-loaded sEVs then accumulate metastatic lesions of the lungs, such as vascular endothelial cells. Lastly, VEGFR2 mRNA is knocked down, and the angiogenesis is suppressed, thereby inhibiting osteosarcoma lung metastasis. The siRNA-expressing backbone could contain siRNA sequences targeting any other disease-associated gene (Figure used with permission from (Yu et al., 2023)).
FIGURE 5 In vivo delivery of an siRNA-expressing genetic circuit. The genetic circuit is comprised of a VEGFR2 siRNA-expressing backbone and a CMV promoter. Following intravenous administration, the anti-VEGFR2 circuit is transported to the liver. In hepatocytes, the CMV promoter controls the transcription of VEGFR2 siRNA and enables the encapsulation of VEGFR2 siRNA into sEVs. After being released into the blood circulation, VEGFR2 siRNA-loaded sEVs then accumulate metastatic lesions of the lungs, such as vascular endothelial cells. Lastly, VEGFR2 mRNA is knocked down, and the angiogenesis is suppressed, thereby inhibiting osteosarcoma lung metastasis. The siRNA-expressing backbone could contain siRNA sequences targeting any other disease-associated gene (Figure used with permission from (Yu et al., 2023)).CC BY · PubMed Central

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Metadata

Authors
Ubanako, P., Mirza, S., Ruff, P., & Penny, C.
Affiliations
University of the Witwatersrand (ZA)
Corresponding author
Penny, Clement
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
Frontiers Media SA
Published
2024-09-17
Volume
11
Pages
1447953-1447953
ISSN
2296-889X (ISSN-L)
DOI
10.3389/fmolb.2024.1447953
PMC
PMC11442288
OpenAlex
W4402604331
Cited by
68
References
234
Citations by year
2026: 35 · 2025: 31 · 2024: 2
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
exosomes, siRNA delivery, extracellular vesicles, cancer therapy, plant-derived exosomes, gene silencing, targeted drug delivery, nanomedicine, clinical translation

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