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Pharmaceutics
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Exosome-Based Drug Delivery: Translation from Bench to Clinic
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Exosome-Based Drug Delivery: Translation from Bench to Clinic

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 23407

Special Issue Editors

Prof. Dr. Chulhee Choi

E-Mail Website
Guest Editor
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Interests: drug development; drug delivery system; extracellular vesicle; immunology; oncology; neurodegenerative disease
Dr. Gi-Hoon Nam

E-Mail Website
Guest Editor
1. Co-Founder/Chief Scientific Officer, ShiftBio Inc., Seoul 02751, Korea
2. Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
Interests: cancer immunotherapy; innovative drug modality; extracellular vesicle; exosome; ferritin

Special Issue Information

Dear Colleagues,

Exosomes derived from various sources can deliver therapeutic agents such as small-molecule drugs, nucleic acids, and proteins to recipient cells by passive or active targeting. By encapsulating active pharmaceutical ingredients inside the phospholipid bilayer of exosomes, we can achieve favorable pharmacokinetic profiles such as prolonged drug half-life and enhanced drug release stability. In addition, exosomes are highly biocompatible and can be used as nanocarriers for tissue-specific targeted delivery. Such abilities have drawn a great deal of attention towards exosomes for therapeutic application for various diseases.

This Special Issue highlights therapeutic exosomes—particularly engineered exosomes for better clinical efficacy. We invite researchers to submit original research articles on therapeutic exosomes focusing on three critical points—1) improving therapeutical efficacy, 2) optimizing tissue targeting and 3) overcoming the limitations of the current production technology for scalable manufacturing. Even though these are the most essential issues to address for developing clinically and commercially viable therapeutic exosomes, research articles on other related issues and review articles on the latest advancements made in the above-mentioned areas are also welcome.

Prof. Dr. Chulhee Choi
Dr. Gi-hoon Nam
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug delivery
  • targeted drug delivery
  • therapeutic exosome
  • manufacturing
  • quality control
  • exosome engineering

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Published Papers (7 papers)

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Research

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21 pages, 5257 KiB  
Article
Extracellular Vesicles and Their Mimetics: A Comparative Study of Their Pharmacological Activities and Immunogenicity Profiles
by Wei Heng Chng, Ram Pravin Kumar Muthuramalingam, Charles Kang Liang Lou, Silas New, Yub Raj Neupane, Choon Keong Lee, Ayca Altay Benetti, Chenyuan Huang, Praveen Thoniyot, Wei Seong Toh, Jiong-Wei Wang and Giorgia Pastorin
Pharmaceutics 2023, 15(4), 1290; https://doi.org/10.3390/pharmaceutics15041290 - 20 Apr 2023
Cited by 3 | Viewed by 2182
Abstract
Extracellular vesicles (EVs), which are miniaturised carriers loaded with functional proteins, lipids, and nucleic acid material, are naturally secreted by cells and show intrinsic pharmacological effects in several conditions. As such, they have the potential to be used for the treatment of various [...] Read more.
Extracellular vesicles (EVs), which are miniaturised carriers loaded with functional proteins, lipids, and nucleic acid material, are naturally secreted by cells and show intrinsic pharmacological effects in several conditions. As such, they have the potential to be used for the treatment of various human diseases. However, the low isolation yield and laborious purification process are obstacles to their translation for clinical use. To overcome this problem, our lab developed cell-derived nanovesicles (CDNs), which are EV mimetics produced by shearing cells through membrane-fitted spin cups. To evaluate the similarities between EVs and CDNs, we compare the physical properties and biochemical composition of monocytic U937 EVs and U937 CDNs. Besides having similar hydrodynamic diameters, the produced CDNs had proteomic, lipidomic, and miRNA profiles with key communalities compared to those of natural EVs. Further characterisation was conducted to examine if CDNs could exhibit similar pharmacological activities and immunogenicity when administered in vivo. Consistently, CDNs and EVs modulated inflammation and displayed antioxidant activities. EVs and CDNs both did not exert immunogenicity when administered in vivo. Overall, CDNs could serve as a scalable and efficient alternative to EVs for further translation into clinical use. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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18 pages, 7958 KiB  
Article
Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice
by Hee-Hoon Kim, Young-Ri Shim, Sung Eun Choi, Tolulope Esther Falana, Jae-Kwang Yoo, So-Hee Ahn, Minhye Park, Hyangmi Seo, Chulhee Choi and Won-Il Jeong
Pharmaceutics 2023, 15(2), 636; https://doi.org/10.3390/pharmaceutics15020636 - 14 Feb 2023
Cited by 7 | Viewed by 3354
Abstract
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called ‘exosomes for protein loading via optically reversible protein–protein interactions (EXPLOR)’ to efficiently deliver [...] Read more.
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called ‘exosomes for protein loading via optically reversible protein–protein interactions (EXPLOR)’ to efficiently deliver the super-repressor IκB-loaded exosomes (Exo-srIκB) to the liver and examined its therapeutic potential in acute-on-chronic alcohol-associated liver injury. We detected enhanced uptake of DiI-labeled Exo-srIκB by LPS-treated inflammatory KCs, which suppressed LPS-induced inflammatory gene expression levels. In animal experiments, a single intravenous injection of Exo-srIκB prior to alcohol binge drinking significantly attenuated alcohol-associated hepatic steatosis and infiltration of neutrophils and macrophages but not a liver injury. Notably, three consecutive days of Exo-srIκB injection remarkably reduced alcohol-associated liver injury, steatosis, apoptosis of hepatocytes, fibrosis-related gene expression levels in hepatic stellate cells, infiltration of neutrophils and macrophages, and inflammatory gene expression levels in hepatocytes and KCs. In particular, the above effects occurred with inhibition of nuclear translocation of NF-κB in liver tissues, and these beneficial effects of Exo-srIκB on ALD were shown regardless of doses. Our results suggest an exosome-based modulation of NF-κB activity in KCs by Exo-srIκB as a novel and efficient therapeutic approach in ALD. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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16 pages, 4823 KiB  
Article
The Effect of Super-Repressor IkB-Loaded Exosomes (Exo-srIκBs) in Chronic Post-Ischemia Pain (CPIP) Models
by Ji Seon Chae, Hyunju Park, So-Hee Ahn, Eun-Chong Han, Yoonjin Lee, Youn Jin Kim, Eun-Jin Ahn, Hye-Won Oh, Hyun Jung Lee, Chulhee Choi, Youn-Hee Choi and Won-joong Kim
Pharmaceutics 2023, 15(2), 553; https://doi.org/10.3390/pharmaceutics15020553 - 7 Feb 2023
Cited by 6 | Viewed by 2800
Abstract
Complex regional pain syndrome (CRPS) is a condition associated with neuropathic pain that causes significant impairment of daily activities and functioning. Nuclear factor kappa B (NFκB) is thought to play an important role in the mechanism of CRPS. Recently, exosomes loaded with super-repressor [...] Read more.
Complex regional pain syndrome (CRPS) is a condition associated with neuropathic pain that causes significant impairment of daily activities and functioning. Nuclear factor kappa B (NFκB) is thought to play an important role in the mechanism of CRPS. Recently, exosomes loaded with super-repressor inhibitory kappa B (Exo-srIκB, IκB; inhibitor of NFκB) have been shown to have potential anti-inflammatory effects in various inflammatory disease models. We investigated the therapeutic effect of Exo-srIκB on a rodent model with chronic post-ischemia pain (CPIP), a representative animal model of Type I CRPS. After intraperitoneal injection of a vehicle, Exo-srIκB, and pregabalin, the paw withdrawal threshold (PWT) was evaluated up to 48 h. Administration of Exo-srIκB increased PWT compared to the vehicle and pregabalin, and the relative densities of p-IκB and IκB showed significant changes compared to the vehicle 24 h after Exo-srIκB injection. The levels of several cytokines and chemokines were reduced by the administration of Exo-srIκB in mice with CPIP. In conclusion, our results showed more specifically the role of NFκB in the pathogenesis of CRPS and provided a theoretical background for novel treatment options for CRPS. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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19 pages, 2337 KiB  
Article
Quantitative Biodistribution and Pharmacokinetics Study of GMP-Grade Exosomes Labeled with 89Zr Radioisotope in Mice and Rats
by Hojun Choi, Myung-Yoon Kim, Dae-Hwan Kim, Hanoul Yun, Byung-Koo Oh, Su-Bin Kim, In-Ho Song, Hyun-Soo Park, Sang-Eun Kim, Cheolhyoung Park and Chulhee Choi
Pharmaceutics 2022, 14(6), 1118; https://doi.org/10.3390/pharmaceutics14061118 - 24 May 2022
Cited by 20 | Viewed by 5682
Abstract
For the successful clinical advancement of exosome therapeutics, the biodistribution and pharmacokinetic profile of exogenous exosomes in various animal models must be determined. Compared with fluorescence or bioluminescence imaging, radionuclide imaging confers multiple advantages for the in vivo tracking of biomolecular therapeutics because [...] Read more.
For the successful clinical advancement of exosome therapeutics, the biodistribution and pharmacokinetic profile of exogenous exosomes in various animal models must be determined. Compared with fluorescence or bioluminescence imaging, radionuclide imaging confers multiple advantages for the in vivo tracking of biomolecular therapeutics because of its excellent sensitivity for deep tissue imaging and potential for quantitative measurement. Herein, we assessed the quantitative biodistribution and pharmacokinetics of good manufacturing practice-grade therapeutic exosomes labeled with zirconium-89 (89Zr) after systemic intravenous administration in mice and rats. Quantitative biodistribution analysis by positron emission tomography/computed tomography and gamma counting in mice and rats revealed that the total 89Zr signals in the organs were lower in rats than in mice, suggesting a higher excretion rate of exosomes in rats. A prolonged 89Zr signal for up to 7 days in most organs indicated that substantial amounts of exosomes were taken up by the parenchymal cells in those organs, highlighting the therapeutic potential of exosomes for the intracellular delivery of therapeutics. Exosomes were mainly distributed in the liver and to a lesser extent in the spleen, while a moderately distributed in the kidney, lung, stomach, intestine, urinary bladder, brain, and heart. Exosomes were rapidly cleared from the blood circulation, with a rate greater than that of free 89Zr, indicating that exosomes might be rapidly taken up by cells and tissues. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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Review

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26 pages, 1660 KiB  
Review
Extracellular Vesicles in Therapeutics: A Comprehensive Review on Applications, Challenges, and Clinical Progress
by Jiyoung Goo, Yeji Lee, Jeongmin Lee, In-San Kim and Cherlhyun Jeong
Pharmaceutics 2024, 16(3), 311; https://doi.org/10.3390/pharmaceutics16030311 - 22 Feb 2024
Cited by 6 | Viewed by 2189
Abstract
Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of [...] Read more.
Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of functions or differentiation of target cells. Owing to these properties, sEVs have recently gained attention as potential carriers for functional molecules and drug delivery tools. However, their use as a therapeutic platform faces limitations, such as challenges in mass production, purity issues, and the absence of established protocols and characterization methods. To overcome these, researchers are exploring the characterization and engineering of sEVs for various applications. This review discusses the origins of sEVs and their engineering for therapeutic effects, proposing areas needing intensive study. It covers the use of cell-derived sEVs in their natural state and in engineered forms for specific purposes. Additionally, the review details the sources of sEVs and their subsequent purification methods. It also outlines the potential of therapeutic sEVs and the requirements for successful clinical trials, including methods for large-scale production and purification. Finally, we discuss the progress of ongoing clinical trials and the implications for future healthcare, offering a comprehensive overview of the latest research in sEV applications. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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29 pages, 2545 KiB  
Review
Exosome-Based Drug Delivery: Translation from Bench to Clinic
by Hee Byung Koh, Hyo Jeong Kim, Shin-Wook Kang and Tae-Hyun Yoo
Pharmaceutics 2023, 15(8), 2042; https://doi.org/10.3390/pharmaceutics15082042 - 29 Jul 2023
Cited by 35 | Viewed by 3617
Abstract
Exosome-based drug delivery is emerging as a promising field with the potential to revolutionize therapeutic interventions. Exosomes, which are small extracellular vesicles released by various cell types, have attracted significant attention due to their unique properties and natural ability to transport bioactive molecules. [...] Read more.
Exosome-based drug delivery is emerging as a promising field with the potential to revolutionize therapeutic interventions. Exosomes, which are small extracellular vesicles released by various cell types, have attracted significant attention due to their unique properties and natural ability to transport bioactive molecules. These nano-sized vesicles, ranging in size from 30 to 150 nm, can effectively transport a variety of cargoes, including proteins, nucleic acids, and lipids. Compared to traditional drug delivery systems, exosomes exhibit unique biocompatibility, low immunogenicity, and reduced toxicity. In addition, exosomes can be designed and tailored to improve targeting efficiency, cargo loading capacity, and stability, paving the way for personalized medicine and precision therapy. However, despite the promising potential of exosome-based drug delivery, its clinical application remains challenging due to limitations in exosome isolation and purification, low loading efficiency of therapeutic cargoes, insufficient targeted delivery, and rapid elimination in circulation. This comprehensive review focuses on the transition of exosome-based drug delivery from the bench to clinic, highlighting key aspects, such as exosome structure and biogenesis, cargo loading methods, surface engineering techniques, and clinical applications. It also discusses challenges and prospects in this emerging field. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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25 pages, 664 KiB  
Review
Small Extracellular Vesicles as a New Class of Medicines
by Inkyu Lee, Yoonjeong Choi, Dong-U Shin, Minjeong Kwon, Seohyun Kim, Hanul Jung, Gi-Hoon Nam and Minsu Kwon
Pharmaceutics 2023, 15(2), 325; https://doi.org/10.3390/pharmaceutics15020325 - 18 Jan 2023
Cited by 10 | Viewed by 2628
Abstract
Extracellular vesicles (EVs) are nanovesicles that are naturally released from cells in a lipid bilayer-bound form. A subset population with a size of 200 nm, small EVs (sEVs), is enticing in many ways. Initially perceived as mere waste receptacles, sEVs have revealed other [...] Read more.
Extracellular vesicles (EVs) are nanovesicles that are naturally released from cells in a lipid bilayer-bound form. A subset population with a size of 200 nm, small EVs (sEVs), is enticing in many ways. Initially perceived as mere waste receptacles, sEVs have revealed other biological functions, such as cell-to-cell signal transduction and communication. Besides their notable biological functions, sEVs have profound advantages as future drug modalities: (i) excellent biocompatibility, (ii) high stability, and (iii) the potential to carry undruggable macromolecules as cargo. Indeed, many biopharmaceutical companies are utilizing sEVs, not only as diagnostic biomarkers but as therapeutic drugs. However, as all inchoate fields are challenging, there are limitations and hindrances in the clinical translation of sEV therapeutics. In this review, we summarize different types of sEV therapeutics, future improvements, and current strategies in large-scale production. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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