MicroRNA therapeutics: towards a new era for the management of cancer and other diseases
Abstract
In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.
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Regulation via miRNA-mediated repression of gene expression is involved in nearly every physiological system and misregulation of miRNA biology is implicated in a broad spectrum of diseases.
“Regulation via miRNA-mediated repression of gene expression has been shown to be involved in nearly every physiological system and misregulation of miRNA biology has been implicated in a broad spectrum of diseases ranging from cancer to neurodegenerative diseases (Quinlan et al., 2017;Rupaimoole and Slack, 2017).”
From Scalable and deep profiling of mRNA targets for individual microRNAs with chimeric eCLIP (2022) · cites this paper as Rupaimoole and Slack, 2017
Dysregulation of miRNA is closely associated with various disease statuses.
“Studies have identified that the dysregulation of miRNA is closely associated with various disease statuses.[237, 238]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [238]
MRG-201 is a synthetic miRNA mimic of miR-29 designed to reduce the expression of collagen and other scar formation related proteins.
“MRG-201 is a synthetic miRNA mimic of miR-29 designed to reduce the expression of collagen and other scar formation related proteins.[238, 241]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [238]
Only a small fraction of preclinical miRNA therapeutics have reached phases of clinical development.
“Although extensive preclinical studies on miRNA therapeutics have been carried out, only a small fraction of them have reached phases of clinical development.[238]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [238]
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BackgroundCRISPR/Cas9 therapeutics: progress and prospects
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“Chemically modified, completely base-paired siRNAs with the identical guide strand sequence as an endogenous miRNA are widely used as miRNA mimics [40].”
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BackgroundMitochondrial Sirtuin 3: New emerging biological function and therapeutic target
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BackgroundEngineered exosomes from different sources for cancer-targeted therapy
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“MicroRNAs (miRNAs) are regarded as regulators of various diseases (Rupaimoole and Slack, 2017).”
BackgroundRNAi-based therapeutics and tumor targeted delivery in cancer
Kara, G., Călin, G. A., & Özpolat, B. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114113 · Cited by 417 · see citing works
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BackgroundInfluentialRNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs
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“Post-myocardial As discussed in the literature [175], the journey of discovering and developing miRNA therapeutics begins with target identification and miRNA discovery through the analysis of patient samples.”
BackgroundTransmiR v2.0: an updated transcription factor-microRNA regulation database
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“In recent years, abundant evidence has shown that the deregulation of specific miRNA is associated with various diseases like cancers (2,4), cardiovascular diseases (5,6), and psychiatric disorders (7,8).”
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“Dysfunction of miRNAs is implicated in different pathological processes, especially in cancer development.((11)) Emerging evidence shows that miRNAs can be actively secreted and delivered into recipient cells, where they block the translation of target genes and thereby affect the activities of recipient cells.”
BackgroundNucleic acid delivery for therapeutic applications
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“This is known as post-transcriptional regulation of gene expression [178].”
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“With the recent development of miRNA inhibitors, including miRNA mimics and anti-miRNAs, which are in clinical trials for human diseases (114), modulation of latent miRNAs or circular RNAs may be effective to inhibit herpesvirus latency.”
BackgroundThe powerful world of antisense oligonucleotides: From bench to bedside
Quéméner, A. M., Bachelot, L., Forestier, A., Donnou‐Fournet, E., Gilot, D., & Galibert, M. (2020) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1594 · Cited by 279 · see citing works
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Rational Design of Nanocarriers for Intracellular Protein Delivery
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Circular RNA vaccine in disease prevention and treatment
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Noncoding RNAs in cancer therapy resistance and targeted drug development
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“The pivotal double-faced roles of miRNAs in cancer make them as both therapeutic candidates and the direct therapeutic targets [17].”
BackgroundRNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential
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Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer
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“miRNA targeting of genes involved in telomere pathway, might enable telomerase activity suppression and cellular senescence and eventually allow the modulation of other relevant cancer gene pathways, contributing more effectively to inhibit cancer cells self-renewal [181, 182].”
Preclinical development of a microRNA-based therapy for intervertebral disc degeneration
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Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases
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The clinical potential of circulating microRNAs in obesity
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MicroRNA-based therapeutics in central nervous system injuries
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“AntimiRs now refer to the modified ASOs having the full or partial complementary reverse sequence of a mature miRNA.(45,95)”
BackgroundNon-coding RNAs in cancer: platforms and strategies for investigating the genomic “dark matter”
Grillone, K., Riillo, C., Scionti, F., Rocca, R., Tradigo, G., Guzzi, P. H., Alcaro, S., Martino, M. T. D., Tagliaferri, P., & Tassone, P. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01622-x · Cited by 253 · see citing works
“MiRNAs are the most extensively studied as both therapeutic candidates or targets [155, 156], followed by lncRNAs, which are emerging in the clinical setting [157–161].”
BackgroundNoncoding <scp>RNA</scp>s in disease
Lekka, E., & Hall, J. (2018) · FEBS Letters · doi:10.1002/1873-3468.13182 · Cited by 251 · see citing works
Therapeutic targeting of non-coding RNAs in cancer
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miRPathDB 2.0: a novel release of the miRNA Pathway Dictionary Database
Kehl, T., Kern, F., Backes, C., Fehlmann, T., Stöckel, D., Meese, E. U., Lenhof, H., & Keller, A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1022 · Cited by 244 · see citing works
“Since the number of miRNAs discovered is steadily rising (7), a remarkable amount of studies already validated microRNA target genes and their function in a multitude of cell-types, tissues and disease phenotypes (8,9).”
BackgroundCurcumin Combination Chemotherapy: The Implication and Efficacy in Cancer
Tan, B. L., & Norhaizan, M. E. (2019) · Molecules · doi:10.3390/molecules24142527 · Cited by 246 · see citing works
“Dysregulation of these molecules can upregulate and downregulate several cellular and molecular targets that lead to the progression of cancer [67].”
BackgroundChallenges identifying efficacious miRNA therapeutics for cancer
Segal, M., & Slack, F. J. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1765770 · Cited by 244 · see citing works
MicroRNAs and metastasis: small RNAs play big roles
Kim, J., Yao, F., Xiao, Z., Sun, Y., & Ma, L. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9712-y · Cited by 236 · see citing works
Slota, J. A., & Booth, S. A. (2019) · Non-Coding RNA · doi:10.3390/ncrna5020035 · Cited by 233 · see citing works
“Indeed, miRNA based therapeutics have been proposed in many complex, difficult to treat disorders such as cancer, heart disease and diabetes in addition to neuroinflammation [202].”
BackgroundDNAzyme-Mediated Assays for Amplified Detection of Nucleic Acids and Proteins
Peng, H., Newbigging, A. M., Wang, Z., Tao, J., Deng, W., Le, X. C., & Zhang, H. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b04926 · Cited by 229 · see citing works
MicroRNA-155—at the Critical Interface of Innate and Adaptive Immunity in Arthritis
Alivernini, S., Gremese, E., McSharry, C. P., Tolusso, B., Ferraccioli, G., McInnes, I. B., & Kurowska‐Stolarska, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01932 · Cited by 226 · see citing works
A Comprehensive Review of Cancer MicroRNA Therapeutic Delivery Strategies
Forterre, A. V., Komuro, H., Aminova, S., & Harada, M. (2020) · Cancers · doi:10.3390/cancers12071852 · Cited by 228 · see citing works
Role of microRNAs in obesity and obesity-related diseases
Iacomino, G., & Siani, A. (2017) · Genes & Nutrition · doi:10.1186/s12263-017-0577-z · Cited by 225 · see citing works
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Yi, D. Y., & Kim, S. (2021) · Nutrients · doi:10.3390/nu13093094 · Cited by 225 · see citing works
“Some of the tens of thousands of known species are reported to be involved in cancer generation, and aberrantly expressed miRNAs in certain types of cancer are emerging as possible biomarkers for diagnosis, treatment, and prognosis of various cancers [81,82].”
BackgroundBose, R. J., Sukumar, U. K., Zeng, Y., Afjei, R., Robinson, E. R., Lau, K. H., Bermudez, A., Habte, F. G., Pitteri, S. J., Sinclair, R., et al. (2018) · ACS Nano · doi:10.1021/acsnano.8b02587 · Cited by 224 · see citing works
mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer
de la Cruz-López, K. G., Toledo-Guzmán, M. E., Sánchez, E. O., & Carrancá, A. G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01373 · Cited by 215 · see citing works
Gene Therapy in Cancer Treatment: Why Go Nano?
Roma‐Rodrigues, C., Rivas‐García, L., Baptista, P. V., & Fernandes, A. R. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12030233 · Cited by 221 · see citing works
“To circumvent the degradation limitations, miRNA may be modified: miRNA mimics are mainly modified by methylation of the passenger strand and locked nucleic acids (LNA) chemistry is used for modification of anti-miRNA (reviewed in [106]).”
BackgroundPaving the Road for RNA Therapeutics
Dammes, N., & Peer, D. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.08.004 · Cited by 220 · see citing works
“For instance, in certain types of cancer, miRNAs that silence oncogenes are downregulated and miRNA mimics can give a therapeutic effect in such cases [22].”
microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches
Leggio, L., Vivarelli, S., L’Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Marchetti, B., & Iraci, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122698 · Cited by 216 · see citing works
The Risks of miRNA Therapeutics: In a Drug Target Perspective
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Tetramethylpyrazine: A review on its mechanisms and functions
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MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications
Martino, M. T. D., Tagliaferri, P., & Tassone, P. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03391-x · Cited by 228 · see citing works
“Introducing anti-miR-21 in such contexts could harm normal cells or even worsen certain conditions, emphasizing the need for thorough evaluation of each miRNA’s roles across different biological settings [7].”
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MicroRNA Therapeutics in Cancer: Current Advances and Challenges
Sayed, S. R. E., Cristante, J., Guyon, L., Denis, J., Chabre, O., & Cherradi, N. (2021) · Cancers · doi:10.3390/cancers13112680 · Cited by 211 · see citing works
Roadmap and strategy for overcoming infusion reactions to nanomedicines
Szebeni, J., Simberg, D., González‐Fernández, Á., Barenholz, Y., & Dobrovolskaia, M. A. (2018) · Nature Nanotechnology · doi:10.1038/s41565-018-0273-1 · Cited by 206 · see citing works
How does hip osteoarthritis differ from knee osteoarthritis?
Hall, M., van der Esch, M., Hinman, R. S., Peat, G., de Zwart, A. H., Quicke, J. G., Runhaar, J., Knoop, J., van der Leeden, M., de Rooij, M., et al. (2021) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2021.09.010 · Cited by 210 · see citing works
Non-coding RNAs in cardiovascular cell biology and atherosclerosis
Fasolo, F., Gregoli, K. D., Mäegdefessel, L., & Johnson, J. L. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz203 · Cited by 202 · see citing works
Kong, Y., Li, Y., Luo, Y., Zhu, J., Zheng, H., Gao, B., Guo, X., Li, Z., Chen, R., & Chen, C. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01205-6 · Cited by 201 · see citing works
Circulating miRNA analysis for cancer diagnostics and therapy
Valihrach, L., Androvic, P., & Kubista, M. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.10.002 · Cited by 199 · see citing works
MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside
To, K. K. W., Tong, C. W. S., Wu, M., & Cho, W. C. S. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i27.2949 · Cited by 195 · see citing works
Classical and noncanonical functions of miRNAs in cancers
Dragomir, M. P., Knutsen, E., & Călin, G. A. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.10.002 · Cited by 194 · see citing works
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A guide to miRNAs in inflammation and innate immune responses
Nejad, C., Stunden, H. J., & Gantier, M. P. (2018) · FEBS Journal · doi:10.1111/febs.14482 · Cited by 192 · see citing works
Recent Advances in Oligonucleotide Therapeutics in Oncology
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“Early studies using naked forms of miRNAs were often unsuccessful due to challenges with degradation and cell delivery [70].”
BackgroundMicrobial dysbiosis in the gut drives systemic autoimmune diseases
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The role of microRNAs in neurodegenerative diseases: a review
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“Some miRNAs show strictly controlled differential spatial and temporal expression patterns and present a more rigorous one (Fabian and Sonenberg 2012; Rupaimoole and Slack 2017).”
BackgroundmiRNAs reshape immunity and inflammatory responses in bacterial infection
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MicroRNAs as modulators of longevity and the aging process
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The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness
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“A mimic of the tumor suppressor, miR-34, has reached phase 1 clinical trials for treating multiple solid tumors, and antimiR-122 has reached phase 2 clinical trials for treating hepatitis C (15).”
BackgroundChemically Modified Platforms for Better RNA Therapeutics
Shi, Y., Zhen, X., Zhang, Y., Li, Y., Koo, S., Saiding, Q., Kong, N., Liu, G., Chen, W., & Tao, W. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00611 · Cited by 184 · see citing works
Deep-belief network for predicting potential miRNA-disease associations
Chen, X., Li, T., Zhao, Y. F., Wang, C.-C., & Zhu, C.-C. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa186 · Cited by 178 · see citing works
- Authors
- Rupaimoole, R., & Slack, F. J.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Slack, Frank J.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2017-02-17
- Volume
- 16
- Issue
- 3
- Pages
- 203-222
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2588025094
- Cited by
- 4,741
- References
- 195
- Citations by year
- 2026: 268 · 2025: 358 · 2024: 425 · 2023: 561 · 2022: 675 · 2021: 787 · 2020: 710 · 2019: 531 · 2018: 309 · 2017: 113
- FWCI
- 46.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- miRNA-based therapy, miRNA mimics, antimiRs, cancer, microRNA dysregulation, tumor suppressor microRNA, oncogenic microRNA, miR-34, miR-122, hepatitis, clinical trials, drug delivery, drug target identification
- MeSH terms
- Animals, Clinical Trials as Topic, Humans, Neoplasms, Genetic Therapy, Disease Management, MicroRNAs
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