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Exosome Biology for Nucleic Acid Medicine—From Bench to Bed

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 45172

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Special Issue Editors

Prof. Dr. Eishi Ashihara

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Guest Editor

Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Misasagi, Yamashina, Kyoto 607-8414, Japan
Interests: molecular targeting therapy; epigenetics; cancer; hematological malignancy; multiple myeloma; cancer stem cell; nucleic acid medicine; drug delivery system; exosome

Prof. Dr. Asako Yamayoshi

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Guest Editor

Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521, Japan
Interests: nucleic acid drugs; chemistry of functional molecules; exosome; material symbiosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Exosomes are lipid bilayer-enclosed extracellular vesicles of approximately 100 nm in diameter and function as cargos for intercellular communication in vivo. They contain mRNA, microRNAs, proteins, lipids, and metabolites. Donor cells secrete exosomes and communicate with each other by transferring the contents to recipient cells. Cancer cells transfer exosomes to surrounding cancerous tissues and alter tumor microenvironments to progress their pathophysiological status. Using this cancer-derived exosome’s nature, therapeutic strategies against them have been investigated.

Nucleic acid medicines, including antisense oligonucleotides, small interfering RNAs, aptamers, and locked nucleic acids, have the potential to therapeutically regulate gene expressions. Development of drug delivery systems (DDSs) is also important to apply nucleic acids to clinical settings, and several useful DDSs have been developed; however, this strategy is limited to treating localized diseases so far. It is essential to develop a powerful DDS for the treatment of cancers.

To address this challenging issue, we focus on our discovery that cancer cell-derived exosomes have a tropism to transfer into cancer cells, and we have developed exosome-capturing antibody-conjugated nucleic acid medicines. This Special Issue will highlight the biology of exosomes and the clinical application of nucleic acid medicines for cancer therapy. We also expect to discuss the possibility to develop novel DDSs using the natures of exosomes.

Prof. Dr. Eishi Ashihara
Prof. Dr. Asako Yamayoshi
Guest Editors

Manuscript Submission Information

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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

exosomes
hematological malignancies
solid tumors
nucleic acid medicines
small interfering RNAs
microRNAs
antibody-conjugated drugs
drug delivery system

Published Papers (12 papers)

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Research

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17 pages, 2595 KiB

Open AccessArticle

Knockdown of 15-bp Deletion-Type v-raf Murine Sarcoma Viral Oncogene Homolog B1 mRNA in Pancreatic Ductal Adenocarcinoma Cells Repressed Cell Growth In Vitro and Tumor Volume In Vivo

by Jiaxuan Song, Yoshiaki Kobayashi, Yoshimasa Asano, Atsushi Sato, Hiroaki Taniguchi and Kumiko Ui-Tei

Cancers 2022, 14(13), 3162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133162 - 28 Jun 2022

Cited by 1 | Viewed by 1576

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second-most common cause of death within the next 10 years. Due to the limited efficacy of available therapies, the survival rate of PDAC patients is very low. Oncogenic BRAF mutations are one of the major causes of PDAC, specifically the missense V600E and L485–P490 15-bp deletion mutations. Drugs targeting the V600E mutation have already been approved by the United States Food and Drug Administration. However, a drug targeting the deletion mutation at L485–P490 of the BRAF gene has not been developed to date. The BxPC-3 cell line is a PDAC-derived cell line harboring wild-type KRAS and L485–P490 deleted BRAF genes. These cells are heterozygous for BRAF, harboring both wild-type BRAF and BRAF with the 15-bp deletion. In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2′-O-methyl modifications at positions 2–5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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14 pages, 2973 KiB

Open AccessArticle

Fusogenic Hybrid Extracellular Vesicles with PD-1 Membrane Proteins for the Cytosolic Delivery of Cargos

by Raga Ishikawa, Shosuke Yoshida, Shin-ichi Sawada, Yoshihiro Sasaki and Kazunari Akiyoshi

Cancers 2022, 14(11), 2635; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112635 - 26 May 2022

Cited by 4 | Viewed by 2436

Abstract

Extracellular vesicles (EVs) are cell-derived lipid membrane capsules that can deliver functional molecules, such as nucleic acids, to target cells. Currently, the application of EVs is limited because of the difficulty of loading cargo into EVs. We constructed hybrid EVs by the fusion of liposomes and insect cell-derived EVs expressing recombinant programmed cell death 1 (PD-1) protein and baculoviral fusogenic glycoprotein gp64, and evaluated delivery of the model cargo molecule, Texas Red-labeled dextran (TR-Dex), into the cytosol. When PD-1 hybrid EVs were added to HeLa cells, the intracellular uptake of the hybrid EVs was increased compared with hybrid EVs without PD-1. After cellular uptake, the PD-1 hybrid EVs were shown to be localized to late endosomes or lysosomes. The results of fluorescence resonance energy transfer (FRET) indicated that membrane fusion between the hybrid EVs and organelles had occurred in the acidic environment of the organelles. When TR-Dex-loaded liposomes were fused with the PD-1 EVs, confocal laser scanning microscopy indicated that TR-Dex was distributed throughout the cells, which suggested that endosomal escape of TR-Dex, through membrane fusion between the hybrid EVs and acidic organelles, had occurred. These engineered PD-1 hybrid EVs have potential as delivery carriers for biopharmaceuticals. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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11 pages, 2835 KiB

Open AccessArticle

Successful Incorporation of Exosome-Capturing Antibody-siRNA Complexes into Multiple Myeloma Cells and Suppression of Targeted mRNA Transcripts

by Emi Soma, Asako Yamayoshi, Yuki Toda, Yuji Mishima, Shigekuni Hosogi and Eishi Ashihara

Cancers 2022, 14(3), 566; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030566 - 23 Jan 2022

Cited by 5 | Viewed by 3535

Abstract

Nucleic acid medicines have been developed as new therapeutic agents against various diseases; however, targeted delivery of these reagents into cancer cells, particularly hematologic cancer cells, via systemic administration is limited by the lack of efficient and cell-specific delivery systems. We previously demonstrated that monoclonal antibody (mAb)-oligonucleotide complexes targeting exosomal microRNAs with linear oligo-D-arginine (Arg) linkers were transferred into solid cancer cells and inhibited exosomal miRNA functions. In this study, we developed exosome-capturing anti-CD63 mAb-conjugated small interfering RNAs (siRNAs) with branched Arg linkers and investigated their effects on multiple myeloma (MM) cells. Anti-CD63 mAb-conjugated siRNAs were successfully incorporated into MM cells. The incorporation of exosomes was inhibited by endocytosis inhibitors. We also conducted a functional analysis of anti-CD63 mAb-conjugated siRNAs. Ab-conjugated luciferase+ (luc+) siRNAs significantly decreased the luminescence intensity in OPM-2-luc+ cells. Moreover, treatment with anti-CD63 mAb-conjugated with MYC and CTNNB1 siRNAs decreased the mRNA transcript levels of MYC and CTNNB1 to 52.5% and 55.3%, respectively, in OPM-2 cells. In conclusion, exosome-capturing Ab-conjugated siRNAs with branched Arg linkers can be effectively delivered into MM cells via uptake of exosomes by parental cells. This technology has the potential to lead to a breakthrough in drug delivery systems for hematologic cancers. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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22 pages, 2993 KiB

Open AccessArticle

Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

by Daniel C. Rabe, Nykia D. Walker, Felicia D. Rustandy, Jessica Wallace, Jiyoung Lee, Shannon L. Stott and Marsha Rich Rosner

Cancers 2021, 13(14), 3459; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143459 - 10 Jul 2021

Cited by 22 | Viewed by 4496

Abstract

Purpose: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. Method: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. Results: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. Conclusion: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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18 pages, 2659 KiB

Open AccessArticle

Long-Term Antitumor CD8⁺ T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles

by Flavia Ferrantelli, Francesco Manfredi, Chiara Chiozzini, Patrizia Leone, Andrea Giovannelli, Eleonora Olivetta and Maurizio Federico

Cancers 2021, 13(9), 2263; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092263 - 08 May 2021

Cited by 6 | Viewed by 2057

Abstract

We developed an innovative method to induce antigen-specific CD8⁺ T cytotoxic lymphocyte (CTL) immunity based on in vivo engineering of extracellular vesicles (EVs). This approach employs a DNA vector expressing a mutated HIV-1 Nef protein (Nef^mut) deprived of the anti-cellular effects typical of the wild-type isoform, meanwhile showing an unusual efficiency of incorporation into EVs. This function persists even when foreign antigens are fused to its C-terminus. In this way, Nef^mut traffics large amounts of antigens fused to it into EVs spontaneously released by the recipient cells. We previously provided evidence that mice injected with a DNA vector expressing the Nef^mut/HPV16-E7 fusion protein developed an E7-specific CTL immune response as detected 2 weeks after the second immunization. Here, we extended and optimized the anti-HPV16 CD8⁺ T cell immune response induced by the endogenously engineered EVs, and evaluated the therapeutic antitumor efficacy over time. We found that the co-injection of DNA vectors expressing Nef^mut fused with E6 and E7 generated a stronger anti-HPV16 immune response compared to that observed in mice injected with the single vectors. When HPV16-E6 and -E7 co-expressing tumor cells were implanted before immunization, all mice survived at day 44, whereas no mice injected with either void or Nef^mut-expressing vectors survived until day 32 after tumor implantation. A substantial part of immunized mice (7 out of 12) cleared the tumor. When the cured mice were re-challenged with a second tumor cell implantation, none of them developed tumors. Both E6- and E7-specific CD8⁺ T immunities were still detectable at the end of the observation time. We concluded that the immunity elicited by engineered EVs, besides counteracting and curing already developed tumors, was strong enough to guarantee the resistance to additional tumor attacks. These results can be of relevance for the therapy of both metastatic and relapsing tumors. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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Review

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15 pages, 1344 KiB

Open AccessReview

Understanding the Role and Clinical Applications of Exosomes in Gynecologic Malignancies: A Review of the Current Literature

by Molly Roy, Yu-Ping Yang, Olivia Bosquet, Sapna K. Deo and Sylvia Daunert

Cancers 2022, 14(1), 158; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010158 - 29 Dec 2021

Cited by 5 | Viewed by 2306

Abstract

Background: Gynecologic malignancies are those which arise in the female reproductive organs of the ovaries, cervix, and uterus. They carry a great deal of morbidity and mortality for patients, largely due to challenges in diagnosis and treatment of these cancers. Although advances in technology and understanding of these diseases have greatly improved diagnosis, treatment, and ultimately survival for patients with gynecologic malignancies over the last few decades, there is still room for improvements in diagnosis and treatment, for which exosomes may be the key. This paper reviews the current knowledge regarding gynecologic tumor derived-exosomal genetic material and proteins, their role in cancer progression, and their potential for advancing the clinical care of patients with gynecologic cancers through novel diagnostics and therapeutics. Literature Review: Ovarian tumor derived exosome specific proteins are reviewed in detail, discussing their role in ovarian cancer metastasis. The key microRNAs in cervical cancer and their implications in future clinical use are discussed. Additionally, uterine cancer-associated fibroblast (CAF)-derived exosomes which may promote endometrial cancer cell migration and invasion through a specific miR-148b are reviewed. The various laboratory techniques and commercial kits for the isolation of exosomes to allow for their clinical utilization are described as well. Conclusion: Exosomes may be the key to solving many unanswered questions, and closing the gaps so as to improve the outcomes of patients with gynecologic cancers around the world. The potential utilization of the current knowledge of exosomes, as they relate to gynecologic cancers, to advance the field and bridge the gaps in diagnostics and therapeutics highlight the promising future of exosomes in gynecologic malignancies. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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18 pages, 1906 KiB

Open AccessReview

Challenges for the Development of Extracellular Vesicle-Based Nucleic Acid Medicines

by Naoya Kuriyama, Yusuke Yoshioka, Shinsuke Kikuchi, Akihiko Okamura, Nobuyoshi Azuma and Takahiro Ochiya

Cancers 2021, 13(23), 6137; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236137 - 06 Dec 2021

Cited by 11 | Viewed by 2572

Abstract

Nucleic acid drugs, such as siRNAs, antisense oligonucleotides, and miRNAs, exert their therapeutic effects by causing genetic changes in cells. However, there are various limitations in their delivery to target organs and cells, making their application to cancer treatment difficult. Extracellular vesicles (EVs) are lipid bilayer particles that are released from most cells, are stable in the blood, and have low immunogenicity. Methods using EVs to deliver nucleic acid drugs to target organs are rapidly being developed that take advantage of these properties. There are two main methods for loading nucleic acid drugs into EVs. One is to genetically engineer the parent cell and load the target gene into the EV, and the other is to isolate EVs and then load them with the nucleic acid drug. Target organ delivery methods include passive targeting using the enhanced permeation and retention effect of EVs and active targeting in which EVs are modified with antibodies, peptides, or aptamers to enhance their accumulation in tumors. In this review, we summarize the advantages of EVs as a drug delivery system for nucleic acid drugs, the methods of loading nucleic acid drugs into EVs, and the targeting of EVs to target organs. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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15 pages, 1359 KiB

Open AccessEditor’s ChoiceReview

MSC-Derived Extracellular Vesicles in Tumors and Therapy

by Tianjiao Luo, Juliane von der Ohe and Ralf Hass

Cancers 2021, 13(20), 5212; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205212 - 18 Oct 2021

Cited by 35 | Viewed by 2901

Abstract

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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19 pages, 650 KiB

Open AccessReview

Nucleic Acid Drugs—Current Status, Issues, and Expectations for Exosomes

by Yoji Yamada

Cancers 2021, 13(19), 5002; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13195002 - 05 Oct 2021

Cited by 40 | Viewed by 5391

Abstract

Nucleic acid drugs are being developed as novel therapeutic modalities. They have great potential to treat human diseases such as cancers, viral infections, and genetic disorders due to unique characteristics that make it possible to approach undruggable targets using classical small molecule or protein/antibody-based biologics. In this review, I describe the advantages, classification, and clinical status of nucleic acid therapeutics. To date, more than 10 products have been launched, and many products have been tested in clinics. To promote the use of nucleic acid therapeutics such as antibodies, several hurdles need to be surmounted. The most important issue is the delivery of nucleic acids and several other challenges have been reported. Recent advanced delivery platforms are lipid nanoparticles and ligand conjugation approaches. With the progress of exosome biology, exosomes are expected to contribute to the solution of various problems associated with nucleic acid drugs. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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23 pages, 5075 KiB

Open AccessReview

Recent Advances in Exosome-Based Drug Delivery for Cancer Therapy

by Hyosuk Kim, Hochung Jang, Haeun Cho, Jiwon Choi, Kwang Yeon Hwang, Yeonho Choi, Sun Hwa Kim and Yoosoo Yang

Cancers 2021, 13(17), 4435; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174435 - 02 Sep 2021

Cited by 49 | Viewed by 8588

Abstract

Exosomes are a class of extracellular vesicles, with a size of about 100 nm, secreted by most cells and carrying various bioactive molecules such as nucleic acids, proteins, and lipids, and reflect the biological status of parent cells. Exosomes have natural advantages such as high biocompatibility and low immunogenicity for efficient delivery of therapeutic agents such as chemotherapeutic drugs, nucleic acids, and proteins. In this review, we introduce the latest explorations of exosome-based drug delivery systems for cancer therapy, with particular focus on the targeted delivery of various types of cargoes. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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31 pages, 1727 KiB

Open AccessReview

Small Extracellular Vesicles and Metastasis—Blame the Messenger

by Tanja Seibold, Mareike Waldenmaier, Thomas Seufferlein and Tim Eiseler

Cancers 2021, 13(17), 4380; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174380 - 30 Aug 2021

Cited by 11 | Viewed by 3143

Abstract

Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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20 pages, 1274 KiB

Open AccessReview

Recent Advances in the Delivery Carriers and Chemical Conjugation Strategies for Nucleic Acid Drugs

by Shota Oyama, Tsuyoshi Yamamoto and Asako Yamayoshi

Cancers 2021, 13(15), 3881; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153881 - 01 Aug 2021

Cited by 11 | Viewed by 4308

Abstract

With the development of new anticancer medicines, novel modalities are being explored for cancer treatment. For many years, conventional modalities, such as small chemical drugs and antibody drugs, have worked by “inhibiting the function” of target proteins. In recent years, however, nucleic acid drugs, such as ASOs and siRNAs, have attracted attention as a new modality for cancer treatment because nucleic acid drugs can directly promote the “loss of function” of target genes. Recently, nucleic acid drugs for use in cancer therapy have been extensively developed and some of them have currently been under investigation in clinical trials. To develop novel nucleic acid drugs for cancer treatment, it is imperative that cancer researchers, including ourselves, cover and understand those latest findings. In this review, we introduce and provide an overview of various DDSs and ligand modification technologies that are being employed to improve the success and development of nucleic acid drugs, then we also discuss the future of nucleic acid drug developments for cancer therapy. It is our belief this review will increase the awareness of nucleic acid drugs worldwide and build momentum for the future development of new cancer-targeted versions of these drugs. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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