Recently, the regulatory effects of microRNAs (miRNAs) on gene expression have been exploited for applications in the diagnosis and treatment of cancer, neurological diseases, and cardiovascular diseases. However, the susceptibility of miRNAs to degradation during somatic circulation and the challenges associated with their delivery to target tissues and cells have limited the clinical application of miRNAs. For application in tumor therapy, it is essential for miRNAs to specifically target cancer cells. Therefore, various novel miRNA delivery systems that protect miRNA against the activity of serum nuclease and deliver miRNA to target cells have been developed and optimized. This review introduces the passive and active targeting strategies of nanoparticles, summarizes the recent progress of miRNA nanocarriers with tumor-targeting ability, and discusses various nanoparticle delivery systems and their antitumor applications. Additionally, this review focuses on the translational challenges and potential strategies for advancing miRNA-based therapies into the clinic.

MicroRNAs (miRNAs) have emerged as pivotal regulators in cancer biology, influencing tumorigenesis, progression, and resistance to therapy. Their ability to modulate multiple oncogenic and tumor-suppressive pathways positions them as promising therapeutic tools or targets. This review examines the dual role of miRNAs in solid and hematological malignancies, starting from their dysregulation in various cancer types. Therapeutic approaches, including miRNA replacement and inhibition strategies, are discussed alongside innovative delivery systems such as lipid nanoparticles and exosomes. Despite their transformative potential, challenges persist, including off-target effects, immune activation, and delivery inefficiencies. Recent clinical trials demonstrate both progress and hurdles, underscoring the need for advanced strategies to optimize specificity and minimize toxicity. This review provides an updated comprehensive overview of the current landscape of miRNA-based therapies under early clinical investigation and explores future directions for integrating these approaches into precision oncology.

Noncoding RNAs (ncRNAs) are a heterogeneous group of RNA molecules whose classification is mainly based on arbitrary criteria such as the molecule length, secondary structures, and cellular functions. A large fraction of these ncRNAs play a regulatory role regarding messenger RNAs (mRNAs) or other ncRNAs, creating an intracellular network of cross-interactions that allow the fine and complex regulation of gene expression. Altering the balance between these interactions may be sufficient to cause a transition from health to disease and vice versa. This leads to the possibility of intervening in these mechanisms to re-establish health in patients. The regulatory role of ncRNAs is associated with all cancer hallmarks, such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Based on the function performed in carcinogenesis, ncRNAs may behave either as oncogenes or tumor suppressors. However, this distinction is not rigid; some ncRNAs can fall into both classes depending on the tissue considered or the target molecule. Furthermore, some of them are also involved in regulating the response to traditional cancer-therapeutic approaches. In general, the regulation of molecular mechanisms by ncRNAs is very complex and still largely unclear, but it has enormous potential both for the development of new therapies, especially in cases where traditional methods fail, and for their use as novel and more efficient biomarkers. Overall, this review will provide a brief overview of ncRNAs in human cancer biology, with a specific focus on describing the most recent ongoing clinical trials (CT) in which ncRNAs have been tested for their potential as therapeutic agents or evaluated as biomarkers.

Cardiovascular complications, particularly diabetic cardiomyopathy (DCM), are the primary causes of morbidity and mortality among individuals with diabetes. Hyperglycemia associated with diabetes leads to cardiomyocyte hypertrophy, apoptosis, and myocardial fibrosis, culminating in heart failure (HF). Patients with diabetes face a 2-4 times greater risk of developing HF compared with those without diabetes. Consequently, there is a growing interest in exploring the molecular mechanisms that contribute to the development of DCM. MicroRNAs (miRNAs) are short, single-stranded, noncoding RNA molecules that participate in the maintenance of physiological homeostasis through the regulation of essential processes such as metabolism, cell proliferation, and apoptosis. At the posttranscriptional level, miRNAs modulate gene expression by binding directly to genes' mRNAs. Multiple cardiac-enriched miRNAs were reported to be dysregulated under diabetic conditions. Different studies revealed the role of specific miRNAs in the pathogenesis of diabetes and related cardiovascular complications, including cardiomyocyte hypertrophy and fibrosis, mitochondrial dysfunction, metabolic impairment, inflammatory response, or cardiomyocyte death. Circulating miRNAs have been shown to represent the potential biomarkers for early detection of diabetic heart injury. A deeper understanding of miRNAs and their role in diabetes-related pathophysiological processes could lead to new therapeutic strategies for addressing cardiac complications associated with diabetes.

Silencing by the miRNA-guided RNA induced silencing complex (miRISC) is dependent on Ago2-chaperoned base pairing between the miRNA 5' seed (5'S) and a complementary sequence in the 3' untranslated region of an mRNA. Prevailing mechanistic understanding posits that initial 5'S pairing can further allow functional base pair expansion into the 3' non-seed (3'NS), while functionally distinct non-canonical pairing was reported between only the 3'NS and the mRNA coding sequence. We developed single-molecule kinetics through equilibrium Poisson sampling (SiMKEPS) to measure highly precise binding and dissociation rate constants of varying-length target sequences to 5'S and 3'NS in a paradigmatic miRISC isolated from human cells, revealing distinct stable states of miRISC with mutually exclusive 5'S and 3'NS pairing. Our data suggest conformational rearrangements of the Ago2-bound miRNA that regulate alternative 5'S- and 3'NS-driven target recognition. The resulting model reconciles previously disparate observations and deepens our acumen for successfully marshaling RNA silencing therapies.

The exploitation of micro-RNA (miR) sequences as therapeutics has become highly attractive for the treatment of several diseases, including those still lacking effective cures such as retinitis pigmentosa (RP). Interestingly, miR-155-5p plays a role in photo-oxidative inflammation in wild-type mice and is up-regulated in rd10 mice showing peak rod degeneration, suggesting its inhibition by the corresponding anti-miR as a viable therapeutic strategy for RP. However, biomedical application of (anti-)miRs is limited by their oligonucleotide nature, suffering from low solubility and bioavailability along with a very low half-life in vivo due to enzymatic degradation. Thereby, the need for suitable delivery systems led to the development of various nanocarriers, including oligosaccharide-based polymers. In this context, we designed and prepared an innovative nanosponge (NS) with a β-cyclodextrin (β-CD) motif payload with a bridge-like molecule, the amphipathic adamantane derivative (ADM), able to establish strong interactions with both NS and the therapeutic miR, thereby delivering and eventually releasing it close to the active site. Through an in vivo study, we both validated the NS system as a useful tool for miR topical administration by eye drop formulation and the functional activity of anti-miR-155-5p in RP.

MicroRNAs (miRNAs) are small noncoding RNAs that are critical for the regulation of multiple physiological and pathological processes, thus holding great clinical potential. However, the therapeutic applications of miRNAs are severely limited by their biological instability and poor intracellular delivery. Herein, we describe a dual-layers surface engineering strategy to design an efficient miRNA delivery nanosystem based on metal-organic frameworks (MOFs) incorporating lipid coating. The resulting nanoparticle system was demonstrated to protect miRNA from ribonuclease degradation, enhance cellular uptake and facilitate lysosomal escape. These ensured effective miRNA mediated gene therapy, which synergized with MOF-specific photodynamic therapy and pre-encapsulated doxorubicin (Dox) chemotherapy to provide a multifunctional with therapeutic effectiveness against cencer cells The mechanisms of miRNA binding and Dox loading were revealed, demonstrating the potential of the present MOFs surface-engineered strategy to overcome their inherent pore-size restriction for macromolecular miRNA carrying, enableefficient co-delivery. In vitro studies revealed the potential of our multifunctional system for miRNA delivery and the demonstrated the therapeutic effectiveness against cancer cells, thereby providing a versatile all-in-one MOFs strategy for delivery of nucleic acids and diverse therapeutic molecules in synergistic therapy.

The identification of specific circulating miRNAs has been proposed as a valuable tool for elucidating the pathophysiology of brain damage or injury and predicting patient outcomes.

This study aims to apply several bioinformatic tools in order to clarify miRNA interactions with potential genes involved in brain injury, emphasizing the need of using a computational approach to determine the most likely correlations between miRNAs and target genes. Specifically, this study centers on elucidating the roles of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a.

After a careful evaluation of different software available (analyzing the strengths and limitations), we applied three tools, one to perform an analysis of the validated targets (miRTarBase), and two to evaluate functional annotations (miRBase and TAM 2.0).

Research findings indicate elevated levels of miR-135a and miR-34b in patients with traumatic brain injury (TBI) within the first day post-injury, while miR-200c and miR-34c were found to be upregulated after 7 days. Moreover, miR-451a and miR-135a were found overexpressed in the serum, while miRNAs 34b, 34c, and 200c, had lower serum levels at baseline post brain injury.

This study emphasizes the use of computational methods in determining the most likely relationships between miRNAs and target genes by investigating several bioinformatic techniques to elucidate miRNA interactions with potential genes. Specifically, this study focuses on the functions of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a, providing an up-to-date overview and suggesting future research directions for identifying theranomiRNAs related to brain injury, both at the tissue and serum levels.

Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis and vein graft failure. Recent advances have unveiled a fascinating range of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. We also discuss the prospects and challenges associated with developing ncRNA-based therapies for this prevalent type of cardiovascular pathology. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.

Intervertebral disc degeneration is the leading cause of low back pain, imposing significant burdens on patients, societies, and economies. Advancements in regenerative medicine have spotlighted extracellular vesicles as promising nanoparticles for intervertebral disc degeneration treatment. Extracellular vesicles retain the potential of cell therapy and serve as carriers to deliver their cargo to target cells, thereby regulating cell activity. This review summarizes the biogenesis and molecular composition of extracellular vesicles and explores their therapeutic roles in intervertebral disc degeneration treatment through various mechanisms. These mechanisms include mitigating cell loss and senescence, delaying extracellular matrix degeneration, and modulating the inflammatory microenvironment. Additionally, it highlights recent efforts in engineering extracellular vesicles to enhance their targeting and therapeutic efficacy. The integration of extracellular vesicle-based acellular therapy is anticipated to drive significant advancements in disc regenerative medicine.

Existing clinical treatment strategies often fail to effectively address the challenges associated with regenerating degenerated intervertebral discs. As a new regenerative medicine strategy, the extracellular vesicle strategy avoids the risks associated with cell transplantation and shows great promise in treating intervertebral disc degeneration by carrying therapeutic cargo. This review comprehensively examines the latest research, underlying mechanisms, and therapeutic potential of extracellular vesicles, offering a promising new strategy for intervertebral disc degeneration treatment.

Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment.

Despite the recent progresses in therapeutic and diagnostic methods, there is still a significantly high rate of mortality among cancer patients. One of the main reasons for the high mortality rate in cancer patients is late diagnosis, which leads to the failure of therapeutic strategies. Therefore, investigation of cancer biology can lead to the introduction of early diagnostic markers in these patients. MicroRNAs (miRNAs) play an important role in regulation of cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, these factors can be considered as the non-invasive tumor markers. Deregulation of miR-382 has been widely reported in different cancers. Therefore, in this review, we investigated the role of miR-382 during tumor development. It has shown that miR-382 has mainly a tumor suppressive, which inhibits the growth of tumor cells through the regulation of signaling pathways, RNA-binding proteins, and transcription factors. Therefore, miR-382 can be suggested as a diagnostic and therapeutic marker in cancer patients.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder, and urinary exosomal microRNAs (miRNAs) were utilized as potential disease prediction or diagnostic biomarkers in numerous studies. This study investigated the differential expression of urinary exosomal miRNAs between non-diabetes mellitus (NDM) individuals and those with T2DM. Aim: To elucidate the association between urinary exosomal miRNAs and T2DM. Methods: We recruited patients diagnosed with T2DM and NDM individuals in West China Hospital, Sichuan University, from November 2023 to February 2024. Subsequently, we performed sequencing of urinary exosomal microRNAs in both groups. The obtained sequencing results were further validated using RT-qPCR in both the training set and the validation set. Additionally, we conducted logistic regression analysis and Spearman correlation analysis on miRNAs with significant differential expression, as well as analysis of their biological functions. Results: A total of 118 urine samples were collected, 59 from individuals diagnosed with T2DM and 59 from NDM. There were differentially expressed miR-183-5p (p = 0.034) and miR-125a-5p (p = 0.008) between the two groups. Furthermore, multivariate regression analysis demonstrated that higher miR-125a-5p levels were negatively associated with the risk of T2DM (p = 0.044; OR: 0.046; 95% CI: 0.002, 0.922). Bioinformatics analysis indicated that the target genes of miR-183-5p were predominantly involved in insulin signaling and glucose transport processes, while those target genes of miR-125a-5p primarily mediated autophagy. Conclusions: miR-183-5p and miR-125a-5p might be involved in the pathogenesis of T2DM, while higher urinary exosomal miR-125a-5p was negatively associated with the risk of T2DM.

Breast cancer is the second leading cause of cancer-related deaths in females worldwide. Despite significant advancements in treatment, drug resistance remains a major challenge, limiting the effectiveness of therapies and leading to dismal outcomes. Approximately 50% of HER2+ breast cancer patients develop resistance to trastuzumab, and patients with triple-negative breast cancer often experience resistance to first-line therapies. The drug resistance mechanisms involve altered drug uptake, enhanced DNA repair, and dysregulated apoptosis pathways. MicroRNAs are essential in regulating cellular processes involved in both homeostasis and disease. Recent data suggest that microRNAs can overcome drug resistance by regulating the pathways that confer drug resistance. Combining different conventional anticancer agents with microRNA therapies holds promise for enhancing treatment effectiveness against drug resistant breast cancer. Advancements in nano-drug delivery systems have facilitated the effective delivery of microRNAs by improving their stability, targeting specific cells, and enhancing cellular uptake. This review elucidates the recent advancements in microRNA-based therapies, their effects on gene expression, and their clinical efficacy in overcoming drug resistance in breast cancer.

Periodontitis is one of the most prevalent oral diseases leading to tooth loss in adults, and is characterized by the destruction of periodontal supporting structures. Traditional therapies for periodontitis cannot achieve ideal regeneration of the periodontal tissue. Mesenchymal stem cells (MSCs) represent a promising approach to periodontal tissue regeneration. Recently, the prominent role of MSCs in this context has been attributed to microRNAs (miRNAs), which participate in post-transcriptional regulation and are crucial for various physiological and pathological processes. Additionally, they function as indispensable elements in extracellular vesicles, which protect them from degradation. In periodontitis, MSCs-derived miRNAs play a pivotal role in cellular proliferation and differentiation, angiogenesis of periodontal tissues, regulating autophagy, providing anti-apoptotic effects, and mediating the inflammatory microenvironment. As a cell-free strategy, their small size and ability to target related sets of genes and regulate signaling networks predispose miRNAs to become ideal candidates for periodontal tissue regeneration. This review aims to introduce and summarize the potential functions and mechanisms of MSCs-derived miRNAs in periodontal tissue repair and regeneration.

The potential of the pericardial space as a therapeutic delivery tool for cardiac fibrosis and heart failure (HF) treatment has yet to be elucidated. Recently, miRNAs and exosomes have been discovered to be present in human pericardial fluid (PF). Novel studies have shown characteristic human PF miRNA compositions associated with cardiac diseases and higher miRNA expressions in PF compared to peripheral blood. Five key studies found differentially expressed miRNAs in HF, angina pectoris, aortic stenosis, ventricular tachycardia, and congenital heart diseases with either atrial fibrillation or sinus rhythm. As miRNA-based therapeutics for cardiac fibrosis and HF showed promising results in several in vivo studies for multiple miRNAs, we hypothesize a potential role of miRNA-based therapeutics delivered through the pericardial cavity. This is underlined by the favorable results of the first phase 1b clinical trial in this emerging field. Presenting the first human miRNA antisense drug trial, inhibition of miR-132 by intravenous administration of a novel antisense oligonucleotide, CDR132L, established efficacy in reducing miR-132 in plasma samples in a dose-dependent manner. We screened the literature, provided an overview of the miRNAs and exosomes present in PF, and drew a connection to those miRNAs previously elucidated in cardiac fibrosis and HF. Further, we speculate about clinical implications and potential delivery methods.

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

Breast cancer is a highly complex disease with multiple subtypes. While many of the breast cancer cases are sporadic some can be familial or hereditary. Genomic integrity is closely monitored by several mechanisms, such as DNA damage machinery and mitotic checkpoints. Any defect in the key genes involved in the regulation of these mechanisms often results in genomic instability, predisposing the cells to malignancy. This results in altered expression of many coding and noncoding genes. The noncoding RNAs especially the long noncoding RNA (lncRNAs) and microRNA (miRNAs) act as key regulators of cancer gene networks. Some miRNAs repress the expression of the heterochromatin-associated proteins, inducing the formation of open chromatin, and promoting the expression of genes required for oncogenesis. Additionally, specific miRNAs may also favour cancer progression and metastasis by regulating the expression of genes that support the metabolic microenvironment essential for cancer cell growth and proliferation. Understanding how these noncoding RNAs contribute to breast cancer development opens potential avenues for therapeutic intervention, targeting their dysregulated activity.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNA (mRNA) molecules and promoting their degradation or blocking their translation. Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. There is increasing evidence to suggest that miRNAs play a role in the pathogenesis of PD. Studies have identified several miRNAs that are dysregulated in the brains of PD patients, and animal models of the disease. MiRNA expression dysregulation contributes to the onset and progression of PD by modulating neuroinflammation, oxidative stress, and protein aggregation genes. Moreover, miRNAs have emerged as potential therapeutic targets for PD. This review elucidates the changes in miRNA expression profiles associated with PD, emphasising their potential as diagnostic biomarkers and therapeutic targets, and detailing specific miRNAs implicated in PD and their downstream targets. Integrated Insights into miRNA Function, Microglial Activation, Diagnostic, and Treatment Prospects in PD Note: This figure is an original figure created by the authors.

Late diagnosis is considered one of the main reasons of high mortality rate among cancer patients that results in therapeutic failure and tumor relapse. Therefore, it is needed to evaluate the molecular mechanisms associated with tumor progression to introduce efficient markers for the early tumor detection among cancer patients. The remarkable stability of microRNAs (miRNAs) in body fluids makes them potential candidates to use as the non-invasive tumor biomarkers in cancer screening programs. MiR-135b has key roles in prognosis and survival of cancer patients by either stimulating or inhibiting cell proliferation, invasion, and angiogenesis. Therefore, in the present review we assessed the molecular biology of miR-135b during tumor progression to introduce that as a novel tumor marker in cancer patients. It has been reported that miR-135b mainly acts as an oncogene by regulation of transcription factors, signaling pathways, drug response, cellular metabolism, and autophagy. This review paves the way to suggest miR-135b as a tumor marker and therapeutic target in cancer patients following the further clinical trials and animal studies.

The dysregulation of miRNAs in lung cancer has been extensively documented, with specific miRNAs acting as both tumor suppressors and oncogenes, depending on their target genes. Recent research has unveiled the regulatory roles of miRNAs in key metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, fatty acid metabolism, and autophagy, which collectively contribute to the aberrant energy metabolism characteristic of cancer cells. Furthermore, miRNAs are increasingly recognized as critical modulators of the tumor microenvironment, impacting immune response and angiogenesis. This review embarks on a comprehensive journey into the world of miRNAs, unraveling their multifaceted roles, and more notably, their emerging significance in the context of cancer, with a particular focus on lung cancer. As we navigate this extensive terrain, we will explore the fascinating realm of miRNA-mediated metabolic rewiring, a phenomenon that plays a pivotal role in the progression of lung cancer and holds promise in the development of novel therapeutic strategies.

Ischemic osteonecrosis, particularly glucocorticoid-induced osteonecrosis of the femoral head (GIONFH), is primarily due to the dysfunction of osteogenesis and angiogenesis. miRNA, as a therapeutic system with immense potential, plays a vital role in the treatment of various diseases. However, due to the unique microenvironmental structure of bone tissue, especially in the case of GIONFH, where there is a deficiency in the vascular system, it is challenging to effectively target and deliver to the ischemic osteonecrosis area. A drug delivery system assisted by genetically engineered cell membranes holds promise in addressing the challenge of targeted miRNA delivery. Herein, we leverage the potential of miR-21 in modulating osteogenesis and angiogenesis to design an innovative biomimetic nanoplatform system. First, we employed metal-organic frameworks (MOFs) as the core structure to load miR-21-m (miR-21-m@MOF). The nanoparticles were further coated with the membrane of bone marrow mesenchymal stem cells overexpressing CXCR4 (CM-miR-21-m@MOF), enhancing their ability to target ischemic bone areas via the CXCR4-SDF1 axis. These biomimetic nanocomposites possess both bone-targeting and ischemia-guiding capabilities, actively targeting GIONFH lesions to release miR-21-m into target cells, thereby silencing PTEN gene and activating the PI3K-AKT signaling pathway to regulate osteogenesis and angiogenesis. This innovative miRNA delivery system provides a promising therapeutic avenue for GIONFH and potentially other related ischemic bone diseases. STATEMENT OF SIGNIFICANCE.

The dark genome, the nonprotein-coding part of the genome, is replete with long noncoding RNAs (lncRNAs). These functionally versatile transcripts, with specific temporal and spatial expression patterns, are critical gene regulators that play essential roles in health and disease. In recent years, FAAH-OUT was identified as the first lncRNA associated with an inherited human pain insensitivity disorder. Several other lncRNAs have also been studied for their contribution to chronic pain and genome-wide association studies are frequently identifying single nucleotide polymorphisms that map to lncRNAs. For a long time overlooked, lncRNAs are coming out of the dark and into the light as major players in human pain pathways and as potential targets for new RNA-based analgesic medicines.

Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) signaling pathways contribute to the development of several cancers, including multiple myeloma (MM). PTEN is a tumor suppressor that influences the PI3K/Akt/mTOR pathway, which in turn impacts vital cellular processes like growth, survival, and treatment resistance. The current study aims to present the role of PTEN and PI3K/Akt/mTOR signaling in the development of MM and its response to treatment. In addition, the molecular interactions in MM that underpin the PI3K/Akt/mTOR pathway and address potential implications for the development of successful treatment plans are also discussed in detail. We investigate their relationship to both upstream and downstream regulators, highlighting new developments in combined therapies that target the PTEN/PI3K/Akt axis to overcome drug resistance, including the use of PI3K and mitogen-activated protein kinase (MAPK) inhibitors. We also emphasize that PTEN/PI3K/Akt pathway elements may be used in MM diagnosis, prognosis, and therapeutic targets.

Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.

microRNAs (miRNAs) represent small RNA molecules involved in the regulation of gene expression. They are implicated in the regulation of diverse cellular processes ranging from cellular homeostasis to stress responses. Unintended irradiation of the cells and tissues, e.g., during medical uses, induces various pathological conditions, including oxidative stress. miRNAs may regulate the expression of transcription factors (e.g., nuclear factor erythroid 2 related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor suppressor protein p53) and other redox-sensitive genes (e.g., mitogen-activated protein kinase (MAPKs), sirtuins (SIRTs)), which trigger and modulate cellular redox signaling. During irradiation, miRNAs mainly act with reactive oxygen species (ROS) to regulate the cell fate. Depending on the pathway involved and the extent of oxidative stress, this may lead to cell survival or cell death. In the context of radiation-induced oxidative stress, miRNA-21 and miRNA-34a are among the best-studied miRNAs. miRNA-21 has been shown to directly target superoxide dismutase (SOD), or NF-κB, whereas miRNA-34a is a direct regulator of NADPH oxidase (NOX), SIRT1, or p53. Understanding the mechanisms underlying radiation-induced injury including the involvement of redox-responsive miRNAs may help to develop novel approaches for modulating the cellular response to radiation exposure.

Non-coding RNAs (ncRNAs) are emerging as biomarkers, molecular signatures, and therapeutic tools and targets for diseases. In this review, we focus specifically on skin diseases to highlight how two classes of ncRNAs-microRNAs and long noncoding RNAs-are being used to diagnose medical conditions of unclear etiology, improve our ability to guide treatment response, and predict disease prognosis. Furthermore, we explore how ncRNAs are being used as both as drug targets and associated therapies have unique benefits, risks, and challenges to development, but offer a distinctive promise for improving patient care and outcomes.

Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy with a complex, multifactorial aetiology. Raised intraocular pressure (IOP) is the most important clinically modifiable risk factor for POAG. All current pharmacological agents target aqueous humour dynamics to lower IOP. Newer therapeutic agents are required as some patients with POAG show a limited therapeutic response or develop ocular and systemic side effects to topical medication. Elevated IOP in POAG results from cellular and molecular changes in the trabecular meshwork driven by increased levels of transforming growth factor β (TGFβ) in the anterior segment of the eye. Understanding how TGFβ affects both the structural and functional changes in the outflow pathway and IOP is required to develop new glaucoma therapies that target the molecular pathology in the trabecular meshwork. In this study, we evaluated the effects of TGF-β1 and -β2 treatment on miRNA expression in cultured human primary trabecular meshwork cells. Our findings are presented in terms of specific miRNAs (miRNA-centric), but given miRNAs work in networks to control cellular pathways and processes, a pathway-centric view of miRNA action is also reported. Evaluating TGFβ-responsive miRNA expression in trabecular meshwork cells will further our understanding of the important pathways and changes involved in the pathogenesis of glaucoma and could lead to the development of miRNAs as new therapeutic modalities in glaucoma.

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.

Diabetes mellitus [DM], is a multifaceted metabolic disease, which has become a worldwide threat to human wellness. Over the past decades, an enormous amount of attention has been devoted to understanding how microRNAs [miRNAs], a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are tied to DM pathology. It has been demonstrated that miRNAs control insulin synthesis, secretion, and activity. This review aims to provide an evaluation of the use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes.

The use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes has been studied, and research that examined this link was sought after in the literature. In addition, we will discuss the cellular and molecular pathways of insulin secretion regulation by miR-143/145 expression and finally their role in diabetes.

In the current review, we emphasize recent findings on the miR-143/145 expression profiles as novel DM biomarkers in clinical studies and animal models and highlight recent discoveries on the complex regulatory effect and functional role of miR-143/145 expression in DM.

A novel clinical treatment that alters the expression and activity of miR-143/miR-145 may be able to return cells to their natural state of glucose homeostasis, demonstrating the value of using comprehensive miRNA profiles to predict the beginning of diabetes.

The online version contains supplementary material available at 10.1007/s40200-023-01317-y.

Cardiovascular diseases (CVDs) stand as the leading cause of death worldwide, posing a significant global health challenge. Consequently, the development of innovative therapeutic strategies to enhance CVDs treatment is imperative. RNA-based therapies, encompassing non-coding RNAs, mRNA, aptamers, and CRISPR/Cas9 technology, have emerged as promising tools for addressing CVDs. However, inherent challenges associated with RNA, such as poor cellular uptake, susceptibility to RNase degradation, and capture by the reticuloendothelial system, underscore the necessity of combining these therapies with effective drug delivery systems. Various non-viral delivery systems, including extracellular vesicles, lipid-based carriers, polymeric and inorganic nanoparticles, as well as hydrogels, have shown promise in enhancing the efficacy of RNA therapeutics. In this review, we offer an overview of the most relevant RNA-based therapeutic strategies explored for addressing CVDs and emphasize the pivotal role of delivery systems in augmenting their effectiveness. Additionally, we discuss the current status of these therapies and the challenges that hinder their clinical translation.

MicroRNA-145 (miR-145) has been reported to downregulate the expression of tissue factor and factor XI in vitro and decrease venous thrombus formation in animal models. However, the association between miR-145 and risk of future venous thromboembolism (VTE) in the general population remains unknown. We investigated the association between plasma levels of miR-145 and risk of future VTE in a case-cohort study. Incident VTE cases (n = 510) and a subcohort (n = 1890) were derived from the third survey of the Trøndelag Health Study (HUNT3), a population-based cohort. The expression levels of miR-145 were measured in plasma samples obtained at baseline. The study population was divided into quartiles based on miR-145 levels in participants in the subcohort, and weighted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma levels of miR-145 were inversely associated with VTE risk. Participants with miR-145 levels in the highest quartile had a 49% lower risk of VTE (HR, 0.51; 95% CI, 0.38-0.68) than those with miR-145 in the lowest quartile in age- and sex-adjusted analysis, and the inverse association was most pronounced for unprovoked VTE (HR, 0.39; 95% CI, 0.25-0.61). Risk estimates remained virtually the same after further adjustment for body mass index, and cancer and arterial cardiovascular disease at baseline. In conclusion, elevated expression levels of miR-145 in plasma were associated with decreased risk of future incident VTE. The protective role of miR-145 against VTE is consistent with previous experimental data and suggests that miR-145 has the potential to be a target for VTE prevention.

Venous thrombosis (VT) is a complex multi-factorial disease and a major health concern worldwide. Its clinical implications include deep vein thrombosis (DVT) and pulmonary embolism (PE). VT pathogenesis involves intricate interplay of various coagulants and anti-coagulants. Growing evidences from epidemiological studies have shown that many non-coding microRNAs play significant regulatory role in VT pathogenesis by modulating expressions of large number of gene involved in blood coagulation. Present study aimed to investigate the effect of human micro RNA (hsa-miR)-320a antagonist on thrombus formation in VT. Surgery was performed on Sprague-Dawley (SD) rats, wherein the inferior vena cava (IVC) was ligated to introduce DVT. Animals were divided into four groups (n = 5 in each group); Sham controls (Sham), IVC ligated-DVT (DVT), IVC ligated-DVT + transfection reagent (DVT-NC) and IVC ligated-DVT + miR320a antagonist (DVT-miR-320a antagonist). IVC was dissected after 6 h and 24 h of surgery to estimate thrombus weight and coagulatory parameters such as levels of D-dimer, clotting time and bleeding time. Also, ELISA based biochemical assays were formed to assess toxicity of miRNA antagonist in animals. Our experimental analysis demonstrated that there was a marked reduction in size of thrombus in hsa-miR-320a antagonist treated animals, both at 6 h and 24 h. There was a marked reduction in D-dimer levels in hsa-miR-320a antagonist treated animals. Also, blood clotting time was delayed and bleeding time was increased significantly in hsa-miR-320a antagonist treated rats compared to the non-treated and Sham rats. There was no sign of toxicity in treated group compared to control animals. Hsa-miR-320a antagonist could be promising therapeutic target for management of VT.

The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.

Using targeted drug delivery systems has emerged as a promising approach to increase the efficacy of chemotherapy, particularly in combination with gene therapy. The overexpression of miR-21 plays a crucial role in colorectal cancer (CRC) progression, and targeted inhibition of miR-21 offers significant potential for enhancing CRC chemotherapy outcomes. In this study, a theranostic system based on mesoporous silica and superparamagnetic iron oxide nanoparticles (SPION@MSNs) was synthesized as a core-shell structure. After loading epirubicin (EPI) in the open pores of MSN, the plasmid expressing anti-miR-21 (pDNA) covered the outer surface with the help of a ZIF-8 (zeolitic imidazolate framework-8) film. Afterward, polyethylene glycol (PEG) and AS1411 aptamer were conjugated to the surface to improve the protective, biocompatibility, and targeting abilities of the nanocarrier. Moreover, the physicochemical characteristics as well as the loading capacity and release profile of EPI and pDNA were fully evaluated. The uptake of the nanoparticles by CRC and normal cell lines in addition to the anticancer effects related to targeted combinational therapy were investigated in vitro. Finally, in vivo tests were performed on BALB/c mice bearing colorectal tumors to evaluate the effectiveness of the targeted nanoparticles, their possible side effects, and also their application in fluorescence and magnetic imaging in vivo. The successful synthesis of SPION@MSN-EPI/pDNA-ZIF-8-PEG-Apt nanoparticles (∼68 nm) and good loading efficiency and controlled release of EPI and pDNA were confirmed. Moreover, hemolysis and gel retardation assays demonstrated the biocompatibility and plasmid protection. Cellular uptake and expression of copGFP illustrated selective entry and transient transfection of targeted nanoparticles, consistent with the cytotoxicity results that indicated the synergistic effects of chemo-gene therapy. The results of animal studies proved the high antitumor efficiency of targeted nanoparticles with minimal tissue damage, which was in line with fluorescence and magnetic imaging results. The novel synthesized nanoparticles containing SPION@MSN-ZIF-8 were suitable for CRC theranostics, and the combined approach of chemo-gene therapy suppressed the tumor more effectively.

To improve their properties or to introduce entirely new functionalities, the intriguing scaffolds of nucleic acids have been decorated with various modifications, most recently also organometallic ones. While challenging to introduce, organometallic modifications offer the potential of expanding the field of application of metal-dependent functionalities to metal-deficient conditions, notably those of biological media. So far, organometallic moieties have been utilized as probes, labels and catalysts. This Feature Article summarizes recent efforts and predicts likely future developments in each of these lines of research.

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Cholangiocarcinoma is a highly aggressive cancer with a dismal prognosis and limited resectability. Chemotherapy has demonstrated tremendous benefits for patients with advanced and inoperable cancer, but drug resistance poses a significant obstacle. Despite recent progress in cancer therapy, the mechanisms driving drug resistance are multifaceted and not completely comprehended. Non-coding RNA refers to RNA molecules that are endogenous and do not code for proteins. Particularly microRNAs, long non-coding RNAs, circular RNAs, are widely acknowledged to be involved in cancer initiation, proliferation, and metastasis. Recently, evidences suggests that abnormal expression of non-coding RNAs contributes to resistance to different type of cancer therapies in cholangiocarcinoma. This occurs via the rewiring of signaling pathways including the reduction of anticancer drugs, apoptosis, interaction between cholangiocarcinoma and tumor-infiltrating immune cells, and cancer stemness. Thus, our review aims to demonstrate the potential of targeting non-coding RNA to override drug resistance and summarize the molecular mechanisms of how non-coding RNA contributes to drug resistance in cholangiocarcinoma.

Allograft rejection is a widespread complication in allograft recipients with chronic kidney disease. Undertreatment of subclinical and clinical rejection and later post-transplant problems are caused by an imperfect understanding of the mechanisms at play and a lack of adequate diagnostic tools. Many different biomarkers have been analyzed and proposed to detect and monitor these crucial events in transplant outcomes. In this sense, microRNAs may help diagnose rejection or tolerance and indicate appropriate treatment, especially in patients with chronic allograft rejection. As key epigenetic regulators of physiological homeostasis, microRNAs have therapeutic potential and may indicate allograft tolerance or rejection. However, more evidence and clinical validation are indispensable before microRNAs are ready for clinical prime time.

Mesenchymal stem cells (MSCs) have tumor-homing ability and play critical roles in tumor treatment, but their dual influences on tumor progression limit their therapeutic applications. Exosomes derived from MSCs (MSC-exosomes) exhibit great potential in targeted tumor treatment due to their advantages of high stability, low immunogenicity, good biocompatibility, long circulation time and homing characteristics. Furthermore, the artificial modification of MSC-exosomes could amplify their advantages and their inhibitory effect on tumors and could overcome the limit of tumor-promoting effect. In this review, we summarize the latest therapeutic strategies involving artificially modified MSC-exosomes in tumor treatment, including employing these exosomes as nanomaterials to carry noncoding RNAs or their inhibitors and anticancer drugs, and genetic engineering modification of MSC-exosomes. We also discuss the feasibility of utilizing artificially modified MSC-exosomes as an emerging cell-free method for tumor treatment and related challenges.

MicroRNAs have emerged as an important regulator of post-transcriptional gene expression studied extensively in many cancers, fetal development, and cardiovascular diseases. Their endogenous nature and easy manipulation have made them potential diagnostic and therapeutic molecules. Diseases with complex pathophysiology such as Diabetic Cardiomyopathy display symptoms at a late stage when the risk of heart failure has become very high. Therefore, the utilization of microRNAs as a tool to study pathophysiology and device-sustainable treatments for DCM could be considered. The present review focuses on the mechanistic insights of diabetic cardiomyopathy and the potential role of microRNAs.

MicroRNAs (miRNAs) control the expression of diverse subsets of target mRNAs, and studies have found miRNA dysregulation in failing hearts. Expression of miR-29 is abundant in heart, increases with aging, and is altered in cardiomyopathies. Prior studies demonstrate that miR-29 reduction via genetic knockout or pharmacologic blockade can blunt cardiac hypertrophy and fibrosis in mice. Surprisingly, this depended on specifically blunting miR-29 actions in cardiomyocytes versus fibroblasts. To begin developing more translationally relevant vectors, we generated a novel transgene-encoded miR-29 inhibitor (TuD-29) that can be incorporated into a viral-mediated gene therapy for cardioprotection. Here, we corroborate that miR-29 expression and activity is higher in cardiomyocytes versus fibroblasts and demonstrate that TuD-29 effectively blunts hypertrophic responses in cultured cardiomyocytes and mouse hearts. Furthermore, we found that adeno-associated virus (AAV)-mediated miR-29 overexpression in mouse hearts induces early diastolic dysfunction, whereas AAV:TuD-29 treatment improves cardiac output by increasing end-diastolic and stroke volumes. The integration of RNA sequencing and miRNA-target interactomes reveals that miR-29 regulates genes involved in calcium handling, cell stress and hypertrophy, metabolism, ion transport, and extracellular matrix remodeling. These investigations support a likely versatile role for miR-29 in influencing myocardial compliance and relaxation, potentially providing a unique therapeutic avenue to improve diastolic function in heart failure patients.

Carcinoma of the lung is among the most common types of cancer globally. Concerning its histology, it is categorized as a non-small cell carcinoma (NSCLC) and a small cell cancer (SCLC) subtype. MicroRNAs (miRNAs) are a member of non-coding RNA whose nucleotides range from 19 to 25. They are known to be critical regulators of cancer via epigenetic control of oncogenes expression and by regulating tumor suppressor genes. miRNAs have an essential function in a tumorous microenvironment via modulating cancer cell growth, metastasis, angiogenesis, metabolism, and apoptosis. Moreover, a wide range of information produced via several investigations indicates their tumor-suppressing, oncogenic, diagnostic assessment, and predictive marker functions in different types of lung malignancy. miRNA mimics or anti-miRNAs can be transferred into a lung cancer cell, with possible curative implications. As a result, miRNAs hold promise as targets for lung cancer treatment and detection. In this study, we investigate the different functions of various miRNAs in different types of lung malignancy, which have been achieved in recent years that show the lung cancer-associated regulation of miRNAs expression, concerning their function in lung cancer beginning, development, and resistance to chemotherapy, also the probability to utilize miRNAs as predictive biomarkers for therapy reaction.