Cancer Letters

Cancer Letters

Volume 489, 1 October 2020, Pages 155-162
Cancer Letters

Commentaries
Functionalized exosome harboring bioactive molecules for cancer therapy

https://doi.org/10.1016/j.canlet.2020.05.036Get rights and content

Highlights

  • Exosomes are promising in drug delivery of bioactive molecules such as chemicals, proteins, and nucleic acids.

  • The advantages of exosomes are stability, biocompatibility, and low immunogeneicity.

  • Exosomes show prolonged half-life and enhanced therapeutic efficacy than other drug delivery platforms.

  • The lipid bilayer membrane structure of exosomes preserves the function of membrane proteins.

  • Exosomes that bear specific surface proteins can penetrate the blood brain barrier and efficiently target tumor tissue.

Abstract

Exosomes are nanosized vesicles with a lipid membrane that are secreted by most cells and play a crucial role as intermediates of intercellular communication because they carry bioactive molecules. Exosomes are promising for drug delivery of chemicals, proteins, and nucleic acids owing to their inherent properties such as excellent biocompatibility, high tumor targetability, and prolonged circulation in vivo. In this review, we cover recent approaches and advances made in the field of exosome-mediated delivery of bioactive molecules for cancer therapy and factors that affect the clinical use of exosomes. This review can be used as a guideline for further study in expanding the utility of therapeutic exosomes.

Introduction

Exosomes are spherical vesicles, 30–150 nm in diameter, produced by most cells in our body, and present in the blood, urine, and cerebrospinal fluid [1]. The biogenesis of exosomes is currently known to occur through the fusion of intracellular multivesicular bodies (MVBs), formed by the inward budding of the late endosome, with the plasma membrane [2]. Exosomes mediate intercellular communication by transporting bioactive molecules, such as nucleic acids, proteins, lipids, and glycoconjugates, which makes exosomes attractive as a potential delivery tool [3,4].

Several studies have been conducted to enhance the delivery of anticancer drugs using nanoparticles, such as synthetic polymers and liposomes [5]. Various drug delivery platforms are under preclinical trials, and there have been very few clinical trials because of inherent limitations, including poor bioavailability and tumor selectivity [6]. Exosomes have superior physical properties relative to other nanoparticles in biocompatibility, stability, and lower immunogenicity [7]. For these reasons, loading or expressing a therapeutic substance in or on exosomes increases its half-life, thereby producing remarkable efficacy by delivering the drugs to the desired target [8,9]. Moreover, since the exosomes generated from cells naturally express parent cell membrane proteins and maintain the cell membrane structure, the efficacy of the therapeutic membrane proteins can be maximized when exposed on the surface of the exosomes [10].

Based on these properties, exosomes have garnered much attention as a promising therapeutic delivery platform for cancer treatment (Fig. 1). Multiple attempts are being made in the production of exosomes as cancer therapy, and several experimental studies indicate that exosomes induce a potent anti-tumor effect over other delivery platforms (Table 1). This review summarizes the relevant examples of exosomes as drug delivery carriers for the treatment of cancer and describes the issues to be addressed in the biotechnology industry for clinical entry.

Section snippets

Nucleic acid delivery

Although nucleic acid drugs are known to have high potential as therapeutic agents, they have a limited clinical application owing to the absence of optimized delivery systems. Delivery of nucleic acids is limited by short half-life, immunogenicity, inability to penetrate physical barriers, insufficient cellular uptake, and delivery to undesired cells leading to off-target gene silencing-mediated toxicity [[11], [12], [13]]. Recently, exosomes have garnered much attention as a suitable platform

Protein delivery

Macromolecular protein therapeutics have been demonstrated to be efficient in the treatment of cancer [32]. Although used widely, protein-based drugs are difficult to purify, with potential solvent toxicity, with the added difficulty in preserving protein activity and stability [33]. The short half-life of therapeutic proteins in vivo also limits efficient cancer therapy [34]. Exosomes can overcome these challenges, with their ability to transport proteins generated from parent cells, long-term

Chemotherapy delivery

Although chemotherapeutic drugs such as doxorubicin and paclitaxel are efficient tumor-suppressors, they have low intratumoral delivery, poor bioavailability, and off-site toxicities [60,61]. Therefore, a new therapeutic approach for targeting and delivering chemotherapy to tumors is desired. Recent studies have shown that exosomes may be used as a therapeutic platform to deliver chemotherapeutics loaded exogenously, such as co-incubation or electroporation [62].

Toffoli et al. also demonstrated

Factors that affect the clinical use of exosomes

Several clinical trials have been attempted over the past decade, using exosomes for cancer therapy (Table 2). However, several questions on the optimization of exosomes for clinical usage remain unanswered, such as how to increase the yield of exosomes specific to cell types and optimize production. Furthermore, it is unclear how to store large therapeutic substances in and on exosomes and how to design a better delivery scheme to specific tissues, in a clinical setting.

Conclusion

Much attention has recently been paid to functionalized exosomes as a drug delivery platform owing to the following. First, exosomes commonly show high stability, high biocompatibility, and low immunogenicity than other drug delivery platforms, leading to a prolonged half-life of therapeutic targets. Second, the lipid bilayer membrane structure of exosomes preserves the function of membrane proteins. Third, nano-sized exosomes that bear specific surface proteins, such as integrins, can

Author contributions

Y.K.K. G.-H.N. and I.-S.K. designed manuscript; Y.K.K. G.-H.N. collated literatures and drafted the manuscript; Y.C. edited the manuscript; I.-S.K. provided oversight and reviewed the manuscript. All authors read and approved the final manuscript.

Declaration of competing interest

The authors declare no competing interests.

Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government [2017R1A3B1023418 and 2018H1A2A1062948]; the KIST Institutional Program; the KU-KIST Graduate School of Converging Science and Technology Program. We would like to thank Editage (www.editage.co.kr) for English language editing.

References (100)

  • S.M. Kim et al.

    Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting

    J. Contr. Release

    (2017)
  • Y. Yang et al.

    Intrinsic cancer vaccination

    Adv. Drug Deliv. Rev.

    (2019)
  • I.L. Colao et al.

    Manufacturing exosomes: a promising therapeutic platform

    Trends Mol. Med.

    (2018)
  • M. Colombo et al.

    Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles

    Annu. Rev. Cell Dev. Biol.

    (2014)
  • N.P. Hessvik et al.

    Current knowledge on exosome biogenesis and release

    Cell. Mol. Life Sci.

    (2018)
  • A.A. Farooqi et al.

    Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds

    Biotechnol. Adv.

    (2018)
  • K. Yuyama et al.

    Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice

    J. Biol. Chem.

    (2014)
  • T.M. Allen et al.

    Liposomal drug delivery systems: from concept to clinical applications

    Adv. Drug Deliv. Rev.

    (2013)
  • Y.W. Cho et al.

    Complex adaptive therapeutic strategy (CATS) for cancer

    J. Contr. Release

    (2014)
  • S. Samanta et al.

    Exosomes: new molecular targets of diseases

    Acta Pharmacol. Sin.

    (2018)
  • S.A.A. Kooijmans et al.

    PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time

    J. Contr. Release

    (2016)
  • N. Yim et al.

    Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module

    Nat. Commun.

    (2016)
  • Y. Yang et al.

    Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery

    J. Extracell. Vesicles

    (2018)
  • T.A. Shtam et al.

    Exosomes are natural carriers of exogenous siRNA to human cells in vitro

    Cell Commun. Signal.

    (2013)
  • S.A.A. Kooijmans et al.

    Exosome mimetics: a novel class of drug delivery systems

    Int. J. Nanomed.

    (2012)
  • D. Castanotto et al.

    The promises and pitfalls of RNA-interference-based therapeutics

    Nature

    (2009)
  • F. Shahabipour et al.

    Exosomes as nanocarriers for siRNA delivery: paradigms and challenges

    Arch. Med. Sci.

    (2016)
  • Y.S. Lee et al.

    MicroRNAs in cancer

    Annu. Rev. Pathol.

    (2009)
  • K. O'Brien et al.

    miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity

    Oncotarget

    (2015)
  • S.I. Ohno et al.

    Systemically injected exosomes targeted to EGFR deliver antitumor microrna to breast cancer cells

    Mol. Ther.

    (2013)
  • Y. Wang et al.

    Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer

    Theranostics

    (2017)
  • T. Yang et al.

    Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio Rerio

    Pharm. Res. (N. Y.)

    (2015)
  • J. Gourlay et al.

    The emergent role of exosomes in glioma

    J. Clin. Neurosci.

    (2017)
  • H. Monfared et al.

    Potential therapeutic effects of exosomes packed with a miR-21-sponge construct in a rat model of glioblastoma

    Front. Oncol.

    (2019)
  • F.M. Lang et al.

    Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas

    Neuro Oncol.

    (2018)
  • P. Liu et al.

    Targeting the untargetable KRAS in cancer therapy

    Acta Pharm. Sin. B.

    (2019)
  • S. Kamerkar et al.

    Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

    Nature

    (2017)
  • M. Mendt et al.

    Generation and testing of clinical-grade exosomes for pancreatic cancer

    JCI Insight

    (2018)
  • T. Yang et al.

    Delivery of small interfering RNA to inhibit vascular endothelial growth factor in zebrafish using natural brain endothelia cell-secreted exosome nanovesicles for the treatment of brain cancer

    AAPS J.

    (2017)
  • H. Li et al.

    Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma

    J. Nanobiotechnol.

    (2018)
  • J. Eoh et al.

    Biomaterials as vectors for the delivery of CRISPR-Cas9

    Biomater. Sci.

    (2019)
  • A. Biagioni et al.

    Delivery systems of CRISPR/Cas9-based cancer gene therapy 11 medical and health sciences 1112 oncology and carcinogenesis

    J. Biol. Eng.

    (2018)
  • Y. Lin et al.

    Exosome–liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs

    Adv. Sci.

    (2018)
  • R. Zaman et al.

    Current strategies in extending half-lives of therapeutic proteins

    J. Contr. Release

    (2019)
  • C.G. Tate

    Practical considerations of membrane protein instability during purification and crystallisation

    Methods Mol. Biol.

    (2010)
  • J.R. Kintzing et al.

    Emerging strategies for developing next-generation protein therapeutics for cancer treatment

    Trends Pharmacol. Sci.

    (2016)
  • M.A. Yildirim et al.

    Drug-target network

    Nat. Biotechnol.

    (2007)
  • J.P. Overington et al.

    How many drug targets are there?

    Nat. Rev. Drug Discov.

    (2006)
  • P. Girard et al.

    A new method for the reconstitution of membrane proteins into giant unilamellar vesicles

    Biophys. J.

    (2004)
  • H.H. Shen et al.

    Reconstitution of membrane proteins into model membranes: seeking better ways to retain protein activities

    Int. J. Mol. Sci.

    (2013)
  • E. Koh et al.

    Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis

    Biomaterials

    (2017)
  • E. Cho et al.

    Comparison of exosomes and ferritin protein nanocages for the delivery of membrane protein therapeutics

    J. Contr. Release

    (2018)
  • Y. Hong et al.

    Exosome as a vehicle for delivery of membrane protein therapeutics, PH20, for enhanced tumor penetration and antitumor efficacy

    Adv. Funct. Mater.

    (2018)
  • Y. Hong et al.

    Degradation of tumour stromal hyaluronan by small extracellular vesicle-PH20 stimulates CD103+ dendritic cells and in combination with PD-L1 blockade boosts anti-tumour immunity

    J. Extracell. Vesicles

    (2019)
  • K. Dooley et al.

    Development of a Platform for Exosome Engineering Using a Novel and Selective Scaffold Protein for Surface Display

    (2019)
  • G.H. Nam et al.

    Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer

    Nat. Commun.

    (2018)
  • E.J. Lee et al.

    Nanocage-therapeutics prevailing phagocytosis and immunogenic cell death awakens immunity against cancer

    Adv. Mater.

    (2018)
  • S.Y. Park et al.

    Harnessing immune checkpoints in myeloid lineage cells for cancer immunotherapy

    Canc. Lett.

    (2019)
  • S. Utsugi-Kobukai et al.

    MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells

    Immunol. Lett.

    (2003)
  • L. Zitvogel et al.

    Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes

    Nat. Med.

    (1998)
  • Cited by (25)

    • Recent developments of nanomedicine delivery systems for the treatment of pancreatic cancer

      2023, Journal of Drug Delivery Science and Technology
      Citation Excerpt :

      In general, exosomes are mainly produced in response to changes in physiological conditions such as cell growth, or pathological conditions, such as cell inflammation or carcinogenesis [124–126]. Exosome source cells define their main features, such as their half-life [127] and composition [114,121], which explain their diverse behaviors. The negative aspect of exosome production occurs in pathological conditions when they are implicated in proliferation, apoptosis, drug resistance, and metastasis [126].

    • Advantage of extracellular vesicles in hindering the CD47 signal for cancer immunotherapy

      2022, Journal of Controlled Release
      Citation Excerpt :

      Consistent with the FACS data, local treatment with EV-SIRPα significantly augmented the infiltration of activated T cells and made the TME favorable to anti-tumorigenic effects by establishing systemic antitumor immunity. EVs can carry drugs inside [35–38], hence the lumen of EV-SIRPα was utilized to load immunogenic cell death (ICD) inducer for combination therapy. The representative ICD inducer, Doxorubicin (Dox), was selected, and calreticulin expression was confirmed in B16F10 cells (Fig. S6).

    • STAT3-EMT axis in tumors: Modulation of cancer metastasis, stemness and therapy response

      2022, Pharmacological Research
      Citation Excerpt :

      As nanostructures, endosomes have a size of 10–160 nm and they are important for preserving homeostasis [334]. The exosomes are able to transport various bioactive molecules among cells to provide cell-cell communication [335]. Proteins, lipids, nucleic acids and glycoconjugates are transported by exosomes among cells [336,337].

    View all citing articles on Scopus
    View full text