miRNA-targeted Therapy Research Articles

Insights into multidrug resistance mechanisms: Exploring distinct miRNAs as prospective therapeutic agents in triple negative breast cancer

Triple Negative Breast Cancer (TNBC) constitutes 12–17 % of breast cancers and is distinguished by the absence of hormone receptor expression, deviating from other breast cancer types. Coupled with its elevated proliferation index, TNBC develops multidrug resistance, diminishing treatment efficacy, weakening disease prognosis, and leading to an aggressive clinical course. This study aimed to assess ABCB1, ABCC1, ABCG2, and ABCC9 gene expression, which play a primary role in the development of multidrug resistance, alongside miRNAs (miR-466, miR-4539, miR-659-3p, miR-3123, miR-3133, and miR-655-3p) targeting these genes. While ABCB1 (p = 0.433), ABCC1 (p < 0.05), and ABCG2 (p < 0.05) exhibited increased expression in tumor tissues, ABCC9 (p = 0.587) did not. miR-466 (p = 0.802), miR-4539 (p = 0.732), miR-659-3p (p = 0.807), and miR-3123 (p = 0.980) were upregulated, whereas miR-3133 (p < 0.05) and miR-655-3p (p = 0.190) were downregulated. Within the scope of our study, we also evaluated the clinical parameters like tumor size, stage, and neoadjuvant treatment that significantly impacted Progression Free Survival (PFS) and Overall Survival (OS). Considering these results, we found that the metastatic status significantly influenced PFS and OS. Chemotherapeutics were found to not affect survival times. Assessing the impact of miRNAs, which we view as potential therapeutic targets, on average survival revealed that elevated miR-3133 expression was correlated with shorter PFS and OS, whereas decreased miR-655-3p expression was associated with longer PFS and OS. In summary, the relevant miRNAs could serve as predictive biomarkers for drug response and aid in developing miRNA-targeted gene therapy strategies.

CRISPR-based dissection of microRNA-23a ~ 27a ~ 24-2 cluster functionality in hepatocellular carcinoma

The miR-23a ~ 27a ~ 24-2 cluster, commonly upregulated in diverse cancers, including hepatocellular carcinoma (HCC), raises questions about the specific functions of its three mature miRNAs and their integrated function. Utilizing CRISPR knockout (KO), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) technologies, we established controlled endogenous miR-23a ~ 27 ~ a24-2 cell models to unravel their roles and signaling pathways in HCC. Both miR-23a KO and miR-27a KO displayed reduced cell growth in vitro and in vivo, revealing an integrated oncogenic function. Functional analysis indicated cell cycle arrest, particularly at the G2/M phase, through the downregulation of CDK1/cyclin B activation. High-throughput RNA-seq, combined with miRNA target prediction, unveiled the miR-23a/miR-27a-regulated gene network, validated through diverse technologies. While miR-23a and miR-27a exhibited opposing roles in cell migration and mesenchymal-epithelial transition, an integrated CRISPRi/a analysis suggested an oncogenic role of the miR-23a ~ 27a ~ 24-2 cluster in cell migration. This involvement potentially encompasses two signaling axes: miR-23a-BMPR2 and miR-27a-TMEM170B in HCC cells. In conclusion, our CRISPRi/a study provides a valuable tool for comprehending the integrated roles and underlying mechanisms of endogenous miRNA clusters, paving the way for promising directions in miRNA-targeted therapy interventions.

The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma.

The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.

MHESMMR: a multilevel model for predicting the regulation of miRNAs expression by small molecules

According to the expression of miRNA in pathological processes, miRNAs can be divided into oncogenes or tumor suppressors. Prediction of the regulation relations between miRNAs and small molecules (SMs) becomes a vital goal for miRNA-target therapy. But traditional biological approaches are laborious and expensive. Thus, there is an urgent need to develop a computational model. In this study, we proposed a computational model to predict whether the regulatory relationship between miRNAs and SMs is up-regulated or down-regulated. Specifically, we first use the Large-scale Information Network Embedding (LINE) algorithm to construct the node features from the self-similarity networks, then use the General Attributed Multiplex Heterogeneous Network Embedding (GATNE) algorithm to extract the topological information from the attribute network, and finally utilize the Light Gradient Boosting Machine (LightGBM) algorithm to predict the regulatory relationship between miRNAs and SMs. In the fivefold cross-validation experiment, the average accuracies of the proposed model on the SM2miR dataset reached 79.59% and 80.37% for up-regulation pairs and down-regulation pairs, respectively. In addition, we compared our model with another published model. Moreover, in the case study for 5-FU, 7 of 10 candidate miRNAs are confirmed by related literature. Therefore, we believe that our model can promote the research of miRNA-targeted therapy.

A novel nanoprobe for visually investigating the controversial role of miRNA-34a as an oncogene or tumor suppressor in cancer cells.

MiRNA-targeted therapy has become a hot topic in current cancer research. The key to this treatment strategy is to clarify the specific role of miRNA in cancer. However, the roles of some miRNAs acting as oncogenic or tumor suppressors are still controversial, which are influenced by different tumor types, even in the same cancer type. Hence, we designed a novel fluorescent nanoprobe based on polydopamine nanoparticles (PDA NPs) for simultaneously detecting caspase-3 and miRNA-34a within living cells. The specific role of miRNA-34a in different cancer cells could be further identified by studying the expression alterations of caspase-3 and miRNA-34a. Confocal imaging indicated that miRNA-34a indeed acted as a tumor suppressor in anticancer drug-treated MCF-7 and HeLa cells, where the effect of miRNA-34a remains controversial. The designed nanoprobe can offer a promising approach to ascertain the oncogenic or tumor-suppressing role of miRNA in different cancer cells with a simple visualization method, which has valuable implications for exploring the practicability of precision therapy focused on miRNA and evaluating the efficacy of new miRNA-targeted anticancer medications.

Intravenous Delivery of miR-21 Inhibitor in Mice With Head and Neck Squamous Cell Carcinoma.

Synthetic miRNA inhibitors have recently attracted considerable interest as potential therapeutic agents for head and neck squamous cell carcinoma. However, due to the lack of evidence, no attempts have been made to deliver these inhibitors intravenously for squamous cell carcinoma. This study investigated whether intravenous administration of a miR-21 inhibitor with lipid nanoparticles could suppress HNSCC in xenograft mice. Head and neck squamous cell carcinoma xenograft mice were intravenously injected with Invivofectamine 3.0® containing either a miR-21 inhibitor or a control inhibitor, using a modified protocol for nucleic acid encapsulation. Quantitative PCR was used to measure the expression level of intratumoral miR-21. And TdT-mediated dUTP nick-end labeling (TUNEL) immunohistochemistry was used to assess cell death. Intravenous injection of miR-21 inhibitor significantly inhibited head and neck squamous cell carcinoma growth and miR-21 expression in tumor tissue compared to the control inhibitor. TUNEL assay showed significant apoptosis of tumor cells after intravenous administration of miR-21 inhibitor. Intravenous delivery of a miR-21 inhibitor with lipid nanoparticles is a promising approach for miRNA-targeted therapy of head and neck squamous cell carcinoma.

MicroRNA-378a-3p plays a regulatory role in trophoblast cell function in preeclampsia by targeting CMTM3

BackgroundPreeclampsia (PE) is a potential multisystemic disease in the middle and late pregnancy. Although its precise etiology and pathogenesis remain unknown, it is a significant cause of morbidity and mortality in both pregnant women and newborns. This study explored the effects of the miR-378a-3p/CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) upon the trophoblast biological functions in PE. MethodsThe placental pathology of PE were identified by hematoxylin-eosin (HE) staining, and miR-378a-3p expression in placental tissues of PE was verified by RT-qPCR. Trophoblast cells (HTR-8/SVneo and JEG-3) were treated with lipopolysaccharide (LPS), and cell counting kit-8 (CCK-8) assay, flow cytometry, scratch assay, and Transwell assay were carried out to measure cell viability, apoptosis, migratory and invasive capacities, respectively. Western blot was performed to determine the expression levels of the cell migration-related proteins. The binding of miR-378a-3p to CMTM3 was verified through a dual-luciferase reporter gene assay. ResultsmiR-378a-3p expression levels were down-regulated in placental tissues and primary trophoblast cells from women with PE compared to the control group. The overexpression of miR-378a-3p promoted the capabilities of LPS-treated trophoblast cells to proliferate, migrate and invade. In contrast, it impeded cell apoptosis, promoted matrix metallopeptidase (MMP)-2 and MMP-9 expression and inhibiting TIMP metallopeptidase inhibitor (TIMP)-1 and TIMP-2 expression. Regarding the molecular mechanism, miR-378a-3p was chosen as the target to modulate the expression level of CMTM3. CMTM3 expression was increased in placental tissues and primary trophoblast cells from women with PE compared to the control group. CMTM3 overexpression could partially neutralize the effects of the overexpressed miR-378a-3p on trophoblast cell function and the expression levels of migration-associated proteins. ConclusionOur study provides a foundation for miRNA-targeted therapy for preeclampsia by establishing for the first time a potential role for the miR-378a-3p/CMTM3 axis in regulating trophoblast cell activities by altering the expression of migration-related proteins.

Visualizing MiRNA Regulation of Apoptosis for Investigating the Feasibility of MiRNA-Targeted Therapy Using a Fluorescent Nanoprobe.

MiRNA-targeted therapy is an active research field in precision cancer therapy. Studying the effect of miRNA expression changes on apoptosis is important for evaluating miRNA-targeted therapy and realizing personalized precision therapy for cancer patients. Here, a new fluorescent nanoprobe was designed for the simultaneous imaging of miRNA-21 and apoptotic protein caspase-3 in cancer cells by using gold nanoparticles as the core and polydopamine as the shell. Confocal imaging indicated that the nanoprobe could be successfully applied for in situ monitoring of miRNA regulation of apoptosis. This design strategy is critical for investigating the feasibility of miRNA-targeted therapy, screening new anti-cancer drugs targeting miRNA, and developing personalized treatment plans.

Simultaneous Visualization of MiRNA-221 and Caspase-3 in Cancer Cells for Investigating the Feasibility of MiRNA-Targeted Therapy with a Dual-Color Fluorescent Nanosensor.

MiRNA-targeted therapy holds great promise for precision cancer therapy. It is important to investigate the effect of changes in miRNA expression on apoptosis in order to evaluate miRNA-targeted therapy and achieve personalized therapy. In this study, we designed a dual-color fluorescent nanosensor consisting of grapheme oxide modified with a molecular beacon and peptide. The nanosensor can simultaneously detect and image miRNA-221 and apoptotic protein caspase-3 in living cells. Intracellular experiments showed that the nanosensor could be successfully applied for in situ monitoring of the effect of miRNA-221 expression changes on apoptosis by dual-color imaging. The current strategy could provide new avenues for investigating the feasibility of miRNA-targeted therapy, screening new anti-cancer drugs targeting miRNA and developing personalized treatment plans.

A NOTCH1/LSD1/BMP2 co-regulatory network mediated by miR-137 negatively regulates osteogenesis of human adipose-derived stem cells

BackgroundMicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs.MethodsDual-luciferase reporter assay was performed to validate the binding to the 3′ untranslated region (3′ UTR) of NOTCH1 by miR-137. To further identify the role of NOTCH1 in miR-137-modulated osteogenesis, tangeretin (an inhibitor of NOTCH1) was applied to treat hASCs which were transfected with miR-137 knockdown lentiviruses, then together with negative control (NC), miR-137 overexpression and miR-137 knockdown groups, the osteogenic capacity and possible downstream signals were examined. Interrelationships between signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1 and BMP2-SMADs were thoroughly investigated with separate knockdown of NOTCH1, LSD1, BMP2, and HES1.ResultsWe confirmed that miR-137 directly targeted the 3′ UTR of NOTCH1 while positively regulated HES1. Tangeretin reversed the effects of miR-137 knockdown on osteogenic promotion and downstream genes expression. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop as well as activated LSD1 and HES1. In addition, LSD1 knockdown induced NOTCH1 expression while suppressed HES1.ConclusionsCollectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

The curious case of miR-155 in SLE.

Epigenetic modifications have been well documented in autoimmune diseases. MicroRNAs (miRNAs), in particular, have long intrigued scientists in the field of autoimmunity. Owing to its central role in the development of the immune system, microRNA-155 (miR-155) is deeply involved in systemic lupus erythematosus (SLE). Despite the advancements made in treating SLE, the disease still remains incurable. Therefore, recent attention has been drawn to the manipulation of epigenetics in the development of curative treatments. In fact, it is a widely held view that miRNA-targeted therapy is a new glimmer of hope in the treatment of autoimmune diseases. However, the duplicity of miRNAs should not be overlooked. A single miRNA can target several mRNAs, and some mRNAs may possess opposing functions. In this review, we highlight the role of miR-155 as a biomarker and review its functions in SLE patients and animal models while discussing possible reasons behind inconsistencies across studies.

A Review of Macrophage MicroRNAs' Role in Human Asthma.

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

MicroRNA in Lung Cancer Metastasis.

Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.

MicroRNAs in Autoimmune Sjögren's Syndrome.

MicroRNAs (miRNAs), small non-coding RNAs, have been implicated in various diseases and cellular functions as microregulators of gene expression. Although the history of miRNA investigation in autoimmune Sjögren’s syndrome (SjS) is fairly short, a substantial amount of data has already been accumulated. These findings clearly indicate potential clinical implications of miRNAs, such as autoantigen expression and autoantibody production, viral miRNAs regulating the calcium signaling pathway, and aberrant immune cell regulation and cytokine production. Research endeavors in the field are currently underway to select disease-specific diagnostic and prognostic biomarkers by utilizing different types of tissues or biological specimens of SjS patients. Various techniques for miRNA analysis with different stringencies have been applied, with the most recent one being next-generation sequencing. This review compiles and highlights differentially-expressed miRNAs in various samples collected from SjS patients and their potential implications in the pathogenesis of SjS. To facilitate the development of miRNA-targeted personalized therapy in the future, we urge more follow-up studies that confirm these findings and elucidate the immunopathological roles of differentially-expressed miRNAs. Furthermore, improved diagnostic criteria for the disease itself will minimize sampling errors in patient recruitment, preventing the generation of inconsistent data.

Prediction of Non-coding RNAs as Drug Targets.

MiRNA is a class of small non-coding RNA molecule that regulates gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in a variety of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapeutics for many human diseases, especially cancers. In this chapter, we introduced a series of computational studies for prediction of small molecule and miRNA associations. Based on different hypotheses, such as transcriptional response similarity, functional consistence or network closeness, the small molecule-miRNA networks were constructed and further analyzed. In addition, several resources that collected experimentally validated relationships or computational predicted associations between small molecules and miRNAs were provided. Collectively, these computational frameworks and databases pave a new way for miRNA-targeted therapy and drug repositioning.

MicroRNAs in Ischemic Heart Disease: From Pathophysiology to Potential Clinical Applications.

Despite rapid advances in cardiovascular research and therapeutic strategies, ischemic heart disease (IHD) remains the leading cause of mortality worldwide. MicroRNAs (miRNAs) are small, noncoding RNAs which post transcriptionally regulate gene expression. In the past few years, miRNAs have emerged as key tools for the understanding of the pathophysiology of IHD, with potential uses as new biomarkers and therapeutic targets. Several studies report a regulatory role of miRNAs, with regard to fundamental components of IHD pathogenesis and progression, such as lipoprotein metabolism, atherogenesis, vascular calcification, platelet function, and angiogenesis. Due to their high stability in biofluids, circulating miRNAs have attracted attention as promising biomarkers of IHD, especially in cardiovascular risk prediction and the diagnosis of myocardial infarction. Furthermore, experimental studies have demonstrated the potential of miRNA-targeted therapy in improving hyperlipidemia, atherosclerosis, and angiogenesis. In this review, the current knowledge on the role of miRNAs in IHD and translational perspectives of their use is discussed.

Invivo visualization of endogenous miR-21 using hyaluronic acid-coated graphene oxide for targeted cancer therapy.

Oncogene-targeted nucleic acid therapy has been spotlighted as a new paradigm for cancer therapeutics. However, invivo delivery issues and uncertainty of therapeutic antisense drug reactions remain critical hurdles for a successful targeted cancer therapy. In this study, we developed a fluorescence-switchable theranostic nanoplatform using hyaluronic acid (HA)-conjugated graphene oxide (GO), which is capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity simultaneously. Cy3-labeled antisense miR-21 peptide nucleic acid (PNA) probes loaded onto HA-GO (HGP21) specifically targeted CD44-positive MBA-MB231cells and showed fluorescence recovery by interacting with endogenous miR-21 in the cytoplasm of the MBA-MB231cells. Knockdown of endogenous miR-21 by HGP21 led to decreased proliferation and reduced migration of cancer cells, as well as the induction of apoptosis, with enhanced PTEN levels. Interestingly, invivo fluorescence signals markedly recovered 3h after the intravenous delivery of HGP21 and displayed signals more than 5-fold higher than those observed in the HGPscr-treated group of tumor-bearing mice. These findings demonstrate the possibility of using the HGP nanoplatform as a cancer theranostic tool in miRNA-targeted therapy.

Identification of associations between small molecule drugs and miRNAs based on functional similarity.

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in varieties of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapy for many human diseases, especially cancer. Here, we proposed a novel computational approach to identify associations between small molecules and miRNAs based on functional similarity of differentially expressed genes. At the significance level of p < 0.01, we constructed the small molecule and miRNA functional similarity network involving 111 small molecules and 20 miRNAs. Moreover, we also predicted associations between drugs and diseases through integrating our identified small molecule-miRNA associations with experimentally validated disease related miRNAs. As a result, we identified 2265 associations between FDA approved drugs and diseases, in which ~35% associations have been validated by comprehensive literature reviews. For breast cancer, we identified 19 potential drugs, in which 12 drugs were supported by previous studies. In addition, we performed survival analysis for the patients from TCGA and GEO database, which indicated that the associated miRNAs of 4 drugs might be good prognosis markers in breast cancer. Collectively, this study proposed a novel approach to predict small molecule and miRNA associations based on functional similarity, which may pave a new way for miRNA-targeted therapy and drug repositioning.

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway.

An increasing number of studies have demonstrated the important role of microRNAs (miRNAs) in modulating cancer progression and metastasis, but the mechanisms by which miRNAs regulate prostate cancer (PCa) tumorigenesis remain poorly understood. In the present study, we found that miR-340 may act as a tumor suppressor based on our finding that it was significantly downregulated in PCa tumor tissues and cell lines. Moreover, the expression of miR-340 was found to be correlated with the inhibition of cell proliferation, migration and invasion in vitro, and had a suppressive effect on tumor growth in a xenograft mouse model as well. The suppressive effect of miR-340 overexpression was observed in cell lines DU145 and BPH-1 which express wild-type (WT) p53. However, in the p53-null PC-3 cell line, the suppressive effect was not found, indicating that miR-340 may play a critical role in the p53 pathway. Further investigation revealed that mouse double minute 2 (MDM2), an important regulator of p53, was targeted by miR-340 through the direct binding to the 3'UTR of MDM2, which inhibited MDM2 translation. In addition, miR-340 expression stabilized p53 protein levels which caused an increase in p21 expression but a decrease in the anti‑apoptotic protein, BCL-2, in the p53 WT cell lines. Moreover, the miR-340-mediated inhibition of cell progression was mitigated by re-expressing MDM2 in the stable miR‑340-overexpressing PCa cell line, which harbors WT p53. Our findings suggest that miR-340 may function as a novel tumor suppressor in PCa through the MDM2-p53 pathway by directly targeting MDM2, which may be a promising miRNA-targeted therapy for PCa.

MiRNA-based therapies: strategies and delivery platforms for oligonucleotide and non-oligonucleotide agents.

The discovery of miRNAs as important regulatory agents for gene expression has expanded the therapeutic opportunities for oligonucleotides. In contrast to siRNA, miRNA-targeted therapy is able to influence not only a single gene, but entire cellular pathways or processes. It is possible to supplement downregulated or non-functional miRNAs by synthetic oligonucleotides, as well as alleviating effects caused by overexpression of malignant miRNAs through artificial antagonists, either oligonucleotides or small molecules. Chemical oligonucleotide modifications together with an efficient delivery system seem to be mandatory for successful therapeutic application. While miRNA-based therapy benefits from the decades of research spent on other therapeutic oligonucleotides, there are some specific challenges associated with miRNA therapy, mainly caused by the short target sequence. The current status and recent progress of miRNA-targeted therapeutics is described and future challenges and potential applications in treatment of cancer and viral infections are discussed.