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Targeting non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), has recently emerged as a promising strategy for treating malignancies and other diseases. In recent years, the development of ncRNA-based therapeutics for targeting protein-coding and non-coding genes has also gained momentum. This review systematically examines ongoing and completed clinical trials to provide a comprehensive overview of the emerging landscape of ncRNA-based therapeutics. Significant efforts have been made to advance ncRNA therapeutics to early clinical studies. The most advanced trials have been conducted with small interfering RNAs (siRNAs), miRNA replacement using nanovector-entrapped miRNA mimics, or miRNA silencing by antisense oligonucleotides. While siRNA-based therapeutics have already received FDA approval, miRNA mimics, inhibitors, and lncRNA-based therapeutics are still under evaluation in preclinical and early clinical studies. We critically discuss the rationale and methodologies of ncRNA targeting strategies to illustrate this rapidly evolving field.

Key Points Mature microRNAs (miRNAs) are single-stranded RNAs that are 19–24 nucleotides in length and are produced in a multistep process involving the ribonuclease enzymes Drosha and Dicer. miRNAs act via diverse mechanisms. In the 'canonical' mechanism, miRNAs bind to the 3′ untranslated (3′ UTR) region of mRNAs and reduce their protein output. Several unexpected mechanisms — such as miRNA binding to other RNA regions or DNA regulatory elements — and direct or indirect upregulation of protein translation have been demonstrated recently. Extracellular miRNAs such as those secreted in exosomes can act on recipient cells through hormone-like mechanisms. miRNAs are drivers or cofactors of carcinogenesis as well as tumour metastasis by controlling the expression of multiple protein-coding genes. Aberrant miRNA expression in cancer can be corrected by replacement using miRNA mimics or blocking with anti-miR approaches. The main advantages of miRNA therapeutics are their multi-targeting effects. Despite substantial challenges associated with miRNA therapeutics, the strategies of replacing tumour suppressor miRNAs with mimics have generated the first miRNA therapeutic agent (MRX34), which is in clinical trials for the treatment of cancer. The combination of miRNAs with chemotherapeutic drugs or small interfering RNAs may synergistically improve the anticancer therapeutic efficacy and can be developed for cancer treatment. Long non-coding RNAs (lncRNAs), including long intergenic ncRNAs (lincRNAs), transcribed ultraconserved regions (T-UCRs) and natural antisense transcripts (NATs), have been found to be involved in human cancers. Many of the lncRNAs are predominately localized in the nucleus and thus act through different mechanisms than miRNAs. The unique features of such lncRNAs can be exploited for the development of specific and novel therapeutic strategies against cancer. Non-coding RNAs (ncRNAs) are involved in the development of a number of diseases, including cancer, and the first ncRNA-targeted therapeutics have recently entered clinical trials. Here, Calin, Ling and Fabbri present the latest insights into ncRNA biology, with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and discuss how these inform therapeutic strategies that modulate ncRNAs in cancer. The first cancer-targeted microRNA (miRNA) drug — MRX34, a liposome-based miR-34 mimic — entered Phase I clinical trials in patients with advanced hepatocellular carcinoma in April 2013, and miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here, we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.

Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.

Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.

Non-coding RNAs (ncRNAs) are a class of RNAs that largely lack the capacity to encode proteins. They have garnered significant attention due to their central regulatory functions across numerous cellular and physiological processes at transcriptional, post-transcriptional, and translational levels. Over the past decade, ncRNA-based therapies have gained considerable attention in the diagnosis, treatment, and prevention of diseases, and many studies have revealed a significant relationship between ncRNAs and diseases. At the same time, due to their tissue specificity, an increasing number of projects have focused on the application of ncRNAs as biomarkers in diseases, as well as the design and development of novel ncRNA-based vaccines and therapies for clinical use. These ncRNAs may also drive research into the potential molecular mechanisms and complex pathogenesis of related diseases. However, new biomarkers need to be validated for their clinical effectiveness. Additionally, to produce safe and stable RNA products, factors such as purity, precise dosage, and effective delivery methods must be ensured to achieve optimal bioactivity. These challenges remain key issues in the clinical application of ncRNAs. This review summarizes the prospects of ncRNAs as potential biomarkers, as well as the current research status and clinical applications of ncRNAs in therapies and vaccines, and discusses the challenges and expectations of ncRNAs in disease diagnosis and drug therapy.

The role of the extracellular non-coding RNAs, particularly microRNAs present in tumor-derived extravesicles, has been intensively exploited in human cancer as a promising tool for diagnostic and prognostic purposes. Current knowledge on exosomes shows an important role not only as vehicles in the intercellular communication, but the transfer of their content can specifically modulate the surrounding microenvironment, leading to tumor development and progression and affecting therapy response. Based on this, much effort has focused on understanding the mechanisms behind the biology of exosomes and their closely interaction with non-coding RNAs as an efficient tool in tumor diagnostic and therapy. Here we summarize the current knowledge on extracellular and exosomes-enclosed non-coding RNAs, and their importance as potential biomarkers and mediators of intercellular communication in tumor biology.

The emergence of SARS-CoV-2 in 2019 has caused a major health and economic crisis around the globe. Gaining knowledge about its attributes and interactions with human host cells is crucial. Non-coding RNAs (ncRNAs) are involved in the host cells’ innate antiviral immune response. In RNA interference, microRNAs (miRNAs) may bind to complementary sequences of the viral RNA strand, forming an miRNA-induced silencing complex, which destroys the viral RNA, thereby inhibiting viral protein expression. There are several targets for human miRNAs on SARS-CoV-2’s RNA, most of which are in the 5’ and 3’ untranslated regions. Mutations of the viral genome causing the creation or loss of miRNA binding sites may have crucial effects on SARS-CoV-2 pathogenicity. In addition to mediating immunity, the ncRNA landscape of host cells further influences their susceptibility to virus infection, as certain miRNAs are essential in the regulation of cellular receptors that are necessary for virus invasion. Conversely, virus infection also changes the host ncRNA expression patterns, possibly augmenting conditions for viral replication and dissemination. Hence, ncRNAs typically upregulated in SARS-CoV-2 infection could be useful biomarkers for disease progression and severity. Understanding these mechanisms could provide further insight into the pathogenesis and possible treatment options against COVID-19.

Currently, for seemingly every type of cancer, dysregulated levels of non-coding RNAs (ncRNAs) are reported and non-coding transcripts are expected to be the next class of diagnostic and therapeutic tools in oncology. Recently, alterations to the ncRNAs transcriptome have emerged as a novel hallmark of cancer. Historically, ncRNAs were characterized mainly as regulators and little attention was paid to the mechanisms that regulate them. The role of modifications, which can control the function of ncRNAs post-transcriptionally, only recently began to emerge. Typically, these modifications can be divided into reversible (i.e., chemical modifications: m5C, hm5C, m6A, m1A, and pseudouridine) and non-reversible (i.e., editing: ADAR dependent, APOBEC dependent and ADAR/APOBEC independent). The first research papers showed that levels of these modifications are altered in cancer and can be part of the tumorigenic process. Hence, the aim of this review paper is to describe the most common regulatory modifications (editing and chemical modifications) of the traditionally considered “non-functional” ncRNAs (i.e., microRNAs, long non-coding RNAs and circular RNAs) in the context of malignant disease. We consider that only by understanding this extra regulatory layer it is possible to translate the knowledge about ncRNAs and their modifications into clinical practice.

Triple-negative breast cancer (TNBC) is characterized by marked clinical and molecular heterogeneity, which underlies the limited success of currently available targeted therapies and results in most patients relying on cytotoxic chemotherapy. This therapeutic gap underscores the pressing need for novel therapeutic approaches, in which non-coding RNAs (ncRNAs) have emerged as promising candidates. In this systematic review, 35 pre-clinical studies published between 2020 and 2025 were analyzed to evaluate the therapeutic potential of targeting ncRNAs in TNBC, including miRNAs, lncRNAs, and circRNAs. The original articles employed in vivo tumor models to assess the therapeutic response of ncRNA expression modulation, using miRNA mimics, antagomiRs, ASOs, shRNAs, and siRNAs integrated into advanced targeted delivery systems, such as nanoparticles and exosomes. According to the selected studies, 28 specific ncRNAs were identified as actionable molecular targets. Modulation of these molecules consistently resulted in tumor growth suppression, metastasis inhibition, and restoration of sensitivity to standard chemotherapeutic agents. Collectively, the pre-clinical evidence presented in these studies positions ncRNA-based therapies as innovative, promising, and potentially effective strategies for advancing TNBC treatment.

Osteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.