Cancer is a major cause of morbidity and mortality, making it one of the most debilitating diseases in our time. Despite advancements in therapeutic strategies, the development of chemoresistance and the occurrence of secondary tumours pose significant challenges. While several promising anti-tumour agents have been identified, their clinical utility is often limited due to toxicity and associated side effects. MicroRNAs (mi-RNAs) are critical regulators of gene expression, and their altered levels are closely linked to cancer development and progression. Although some microRNAs have shown potential as biomarkers for cancer detection, their integration into routine clinical practice has yet to be realized. Numerous candidate microRNAs exhibit therapeutic potential for cancer treatment; however, further research is needed to create efficient, patient-compliant, and customized drug delivery systems. In recent decades, various nanotechnology platforms have successfully transitioned to clinical trials, particularly in the field of RNA nanotechnology. Several RNA nanoparticles have been developed to address key challenges in vivo for targeting cancer, demonstrating favourable biodistribution characteristics. Studies have shown that RNA nanoparticles, characterized by precise stoichiometry and homogeneity, can effectively target tumour cells while avoiding aggregation in normal, healthy tissues following systemic injection. Animal models have demonstrated that RNA nanoparticles can deliver therapeutics such as siRNA and anti-microRNA, effectively inhibiting tumour growth. Using nanoparticles conjugated with antibodies and/or peptides enhances the targeted delivery and sustained release of microRNAs and anti-microRNAs, which may reduce the required therapeutic dosage and minimize systemic and cellular damage. This review focuses on developing microRNA nanoformulations to improve cellular uptake, bioavailability, and accumulation at tumour sites, assessing their potential anti-tumour efficacy against various types of malignancies. The significance of these advancements in clinical oncology cannot be overstated.

Cardiovascular disease remains the leading cause of death worldwide, with atherosclerosis (AS) serving as a critical underlying pathological process and major risk factor. Regular physical exercise is widely recognized as an effective strategy to reduce the risks and severity of AS, yet the precise molecular mechanisms through which exercise exerts its protective effects are still not fully understood. MicroRNAs (miRNAs), key regulators of gene expression, play integral roles in the progression of AS by influencing vascular function, lipid metabolism, and inflammation. The exercise-induced improvement of AS is a complex process, with miRNAs playing essential roles not only within cells and tissues but also circulating stably in the bloodstream as novel signaling molecules. These circulating miRNAs mediate communication between organs and tissues, acting as potential biomarkers that could provide deeper, systemic insights into the metabolic benefits of exercise. In this review, we explore recent advancements in our understanding of how exercise affects both intracellular and circulating miRNAs. We emphasize how exercise-regulated miRNAs contribute to endothelial function, promote lipid metabolism across various metabolic organs, and reduce monocyte-mediated systemic inflammation, while also addressing their role in alleviating frailty. Circulating miRNAs, which dynamically reflect tissue-specific responses to exercise, hold great promise as diagnostic and prognostic biomarkers for AS. Moreover, we discuss the challenges and future directions in this field, aiming to uncover how exercise-induced miRNA modulation could offer innovative therapeutic strategies for the prevention and treatment of AS.

Alzheimer's disease (AD) is a neurological disorder that affects cognition and behavior, accounting for 60-70 % of dementia cases. Its mechanisms involve amyloid aggregates, hyperphosphorylated tau tangles, and loss of neural connections. Current treatments have limited efficacy due to a lack of specific targets. Recently, microRNAs (miRNAs) have emerged as key modulators in AD, regulating gene expression through interactions with mRNA. Dysregulation of specific miRNAs contributes to disease progression by disrupting clearance pathways. Antisense oligonucleotide (ASO)-based therapies show promise for AD treatment, particularly when combined with miRNA mimics or antagonists, targeting complex regulatory networks. However, miRNAs can interact with each other, complicating cellular processes and potentially leading to side effects. Our review emphasizes the role of miRNAs in regulating amyloid-beta (Aβ) clearance and highlights their potential as therapeutic targets and early biomarkers for AD, underscoring the need for further research to enhance their efficacy and safety.

Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.

Recent advancements in microRNAs (miRNAs) research have revealed their key roles in both normal physiological processes and pathological conditions, leading to potential applications in diagnostics and therapeutics. However, the path forward is fraught with several scientific and technical challenges. This review article briefly explores the milestones of the discovery, biogenesis, functions, and application for clinical diagnostic and therapeutic strategies of miRNAs. The potential challenges and future directions are also discussed to fully harness their capabilities.

Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.

Schizophrenia is a complex psychiatric disorder, and genetic and environmental factors have been implicated in its development. Dysregulated glutamatergic and dopaminergic transmission pathways are involved in schizophrenia development. Besides genetic mutations, epigenetic dysregulation has a considerable role in dysregulating molecular pathways involved in schizophrenia. MicroRNAs (miRNAs) are small, non-coding RNAs that target specific mRNAs and inhibit their translation into proteins. As epigenetic factors, miRNAs regulate many genes involved in glutamate and dopamine signaling pathways; thereby, their dysregulation can contribute to the development of schizophrenia. Secretion of specific miRNAs from damaged cells into body fluids can make them one of the ideal non-invasive biomarkers in the early diagnosis of schizophrenia. Also, understanding the molecular mechanisms of miRNAs in schizophrenia pathogenesis can pave the way for developing novel treatments for patients with schizophrenia. In this study, we reviewed the glutamatergic and dopaminergic pathophysiology and highlighted the role of miRNA dysregulation in schizophrenia development. Besides, we shed light on the significance of circulating miRNAs for schizophrenia diagnosis and the recent findings on the miRNA-based treatment for schizophrenia.

The long noncoding RNA (lncRNA) HOTAIR has been shown to act as an oncogene in a variety of cancers, including hepatocellular carcinoma (HCC). MicroRNA-122 (miR-122) is a key liver-specific miRNA that is frequently inhibited in HCC and is associated with poor prognosis. However, a potential relationship between HOTAIR and miR-122 in individual hepatocytes has not been explored. To this end, we propose here an intracellular catalytic hairpin self-assembly-CRISPR/Cas12a tandem multiplexed signal amplification strategy for the simultaneous quantification of HOTAIR and miRNA-122 in a single hepatocyte. We applied this method to analyze both normal HL-7702 liver cells and HepG2 HCC cells, and found that HL-7702 cells contained large amounts of miRNA-122, while the content of miRNA-122 in HepG2 cells was low. However, the level of HOTAIR in HepG2 cells was much higher than that in HL-7702 cells, confirming the overexpression of HOTAIR in HCC cells. We achieved the simultaneous absolute quantification of HOTAIR and miRNA-122 in single cells, providing an important method to study the relationships between these two RNA molecules in individual cells.

RNA molecules in the cell are bound by a multitude of RNA-binding proteins (RBPs) with a variety of regulatory consequences. Often, interactions with these RNA-binding proteins are facilitated by the complex secondary and tertiary structures of RNA molecules. Viral RNAs especially are known to be heavily structured and interact with many RBPs, with roles including genome packaging, immune evasion, enhancing replication and transcription, and increasing translation efficiency. As such, the RNA-protein interactome represents a critical facet of the viral replication cycle. Characterization of these interactions is necessary for the development of novel therapeutics targeted at the disruption of essential replication cycle events. In this review, we aim to summarize the various roles of RNA structures in shaping the RNA-protein interactome, the regulatory roles of these interactions, as well as up-to-date methods developed for the characterization of the interactome and directions for novel, RNA-directed therapeutics.

Long noncoding RNAs (LncRNAs) play essential roles in regulating gene expression in various biological processes. However, the function of lncRNAs in vascular smooth muscle cell (VSMC) transformation remains to be explained. In this work, we discover that a new bone marrow protein (BMP) signaling target, lncRNA RP11-301G19.1, is significantly induced in BMP7-treated VSMCs through lncRNA microarray analysis. Addition of BMP signaling inhibitor LDN-193189 attenuates the expression of ACTA2 and SM-22α, as well as the mRNA level of RP11-301G19.1. Furthermore, lncRNA RP11-301G19.1 is critical to the VSMC differentiation and is directly activated by SMAD1/9. Mechanistically, knocking down of RP11-301G19.1 leads to the decrease of ATOH8, another BMP target, while the forced expression of RP11-301G19.1 reactivates ATOH8. In addition, miR-17-5p, a miRNA negatively regulated by BMP-7, contains predicted binding sites for lncRNA RP11-301G19.1 and ATOH8 3'UTR. Accordingly, overexpression of miR-17-5p decreases the levels of them. Together, our results revealed the role of lncRNA RP11-301G19.1 as a miRNA sponge to upregulate ATOH8 in VSMC phenotype transformation.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Alterations of hepatic microRNA (miRNA) expression/activity significantly contribute to the development and progression of MASLD. Genetic polymorphisms of miR-149 are associated with an increased susceptibility to MASLD development in humans. Aberrant expression of miR-149 was also associated with metabolic alterations in several organs, but the impact of hepatic miR-149-5p deregulation in MASLD remains poorly characterized.

MiR-149-5p was downregulated in the livers of mice by in vivo transduction with hepatotropic adeno-associated virus 8 harboring short-hairpin RNAs (shRNAs) specific for miR-149-5p (shmiR149) or scrambled shRNAs (shCTL). MASLD was then induced with a methionine/choline-deficient (MCD, n = 7 per group) diet or a fructose/palmitate/cholesterol-enriched (FPC, n = 8-12 per group, per protocol) diet. The impact of miR-149-5p modulation on MASLD development was assessed in vivo and in vitro using multi-lineage 3D human liver organoids (HLOs) and Huh7 cells.

MiR-149-5p expression was strongly upregulated in mouse livers from different models of MASLD (2-4-fold increase in ob/ob, db/db mice, high-fat and FPC-fed mice). In vivo downregulation of miR-149-5p led to an amelioration of diet-induced hepatic steatosis, inflammation/fibrosis, and to increased whole-body fatty acid consumption. In HLOs, miR-149-5p overexpression promoted lipid accumulation, inflammation and fibrosis. In vitro analyses of human Huh7 cells overexpressing miR-149-5p indicated that glycolysis and intracellular lipid accumulation was promoted, while mitochondrial respiration was impaired. Translatomic analyses highlighted deregulation of multiple potential miR-149-5p targets in hepatocytes involved in MASLD development.

MiR-149-5p upregulation contributes to MASLD development by affecting multiple metabolic/inflammatory/fibrotic pathways in hepatocytes. Our results further demonstrate that HLOs are a relevant 3D in vitro model to investigate hepatic steatosis and inflammation/fibrosis development.

Our research shows compelling evidence that miR-149-5p plays a pivotal role in the development and progression of MASLD. By employing in vivo and innovative in vitro models using multi-lineage human liver organoids, we demonstrate that miR-149-5p upregulation significantly impacts hepatocyte energy metabolism, exacerbating hepatic steatosis and inflammation/fibrosis by modulating a wide network of target genes. These findings not only shed light on the intricate miR-149-5p-dependent molecular mechanisms underlying MASLD, but also underscore the importance of human liver organoids as valuable 3D in vitro models for studying the disease's pathogenesis.

To eradicate atherosclerotic diseases, novel biomarkers, and future therapy targets must reveal the burden of early atherosclerosis (AS), which occurs before life-threatening unstable plaques form. The chemical and biological features of microRNAs (miRNAs) make them interesting biomarkers for numerous diseases. We summarized the latest research on miRNA regulatory mechanisms in AS progression studies, which may help us use miRNAs as biomarkers and treatments for difficult-to-treat diseases.

Recent research has demonstrated that miRNAs have a regulatory function in the observed changes in gene and protein expression during atherogenesis, the process that leads to atherosclerosis. Several miRNAs play a role in the development of atherosclerosis, and these miRNAs could potentially serve as non-invasive biomarkers for atherosclerosis in various regions of the body. These miRNAs have the potential to serve as biomarkers and targets for early treatment of atherosclerosis. The start and development of AS require different miRNAs. It reviews new research on miRNAs affecting endothelium, vascular smooth muscle, vascular inflammation, lipid retention, and cholesterol metabolism in AS. A miRNA gene expression profile circulates with AS everywhere. AS therapies include lipid metabolism, inflammation reduction, and oxidative stress inhibition. Clinical use of miRNAs requires tremendous progress. We think tiny miRNAs can enable personalized treatment.

Recurrent implantation failure (RIF) is a significant obstacle in assisted reproductive procedures, primarily because of compromised receptivity. As such, there is a need for a dependable and accurate clinical test to evaluate endometrial receptiveness, particularly during embryo transfer. MicroRNAs (miRNAs) have diverse functions in the processes of implantation and pregnancy. Dysregulation of miRNAs results in reproductive diseases such as recurrent implantation failure (RIF). The endometrium secretes several microRNAs (miRNAs) during the implantation period, which could potentially indicate whether the endometrium is suitable for in vitro fertilization (IVF). The goal of this review is to examine endometrial miRNAs as noninvasive biomarkers that successfully predict endometrium receptivity in RIF.

Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The precise etiology of PD remains unclear, but emerging evidence suggests a significant role for disrupted autophagy-a crucial cellular process for maintaining protein and organelle integrity.

This review focuses on the role of non-coding RNAs (ncRNAs) in modulating autophagy in PD. We conducted a comprehensive review of recent studies to explore how ncRNAs influence autophagy and contribute to PD pathophysiology. Special attention was given to the examination of ncRNAs' regulatory impacts in various PD models and patient samples.

Findings reveal that ncRNAs are pivotal in regulating key processes associated with PD progression, including autophagy, α-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation. Dysregulation of specific ncRNAs appears to be closely linked to these pathogenic processes.

ncRNAs hold significant therapeutic potential for addressing autophagy-related mechanisms in PD. The review highlights innovative therapeutic strategies targeting autophagy-related ncRNAs and discusses the challenges and prospective directions for developing ncRNA-based therapies in clinical practice. The insights from this study underline the importance of ncRNAs in the molecular landscape of PD and their potential in novel treatment approaches.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.

Afamin is a hepatokine that involves in glucose and lipids metabolism. miR-122 is mainly expressed in liver and involves in lipid and carbohydrate metabolism. This study aimed at investigating the circulating afamin, its correlation with type 2 diabetes mellitus (T2DM) and miR-122 gene expression in T2DM patients and healthy control subjects according to the duration of diabetes.

This case-control study included 220 participants, with 100 individuals serving as controls and 120 individuals diagnosed with type 2 diabetes mellitus (T2DM). The miR-122 gene expression was assessed using real-time PCR. The serum concentration of biochemical parameters such as glucose levels, lipid profile, and small-dense low-density lipoprotein (sdLDL) were measured using colorimetric kits. Circulating afamin and insulin levels were assayed using an ELISA kit. Glycated hemoglobin (HbA1c) was measured using capillary electrophoresis.

Circulating afamin level was significantly higher in T2DM patients compared to the control group, (73.8 ± 10.8 vs. 65.9 ± 8.7, respectively; P < 0.001). Similarly, miR122 expression was significantly increased in T2DM patients compared to healthy control subjects (4.24 ± 2.01 vs. 1.00 ± 0.85, respectively; P < 0.001). Among patients diagnosed with T2DM, those with longstanding diabetes (>5 years) exhibited significantly higher levels of circulating afamin and miR-122 expression compared to individuals with a shorter duration of diabetes (≤5 years) (P < 0.05). Circulating afamin levels were significantly correlated with waist circumference, small-dense low-density lipoprotein (sdLDL), fasting blood sugar (FBS), insulin, resistance to insulin, and miR-122 expression, depending on the duration of the disease (P < 0.05). Furthermore, the performance of afamin as a diagnostic marker for T2DM was confirmed through receiver operating characteristic (ROC) analysis, yielding an area under the curve (AUC) of 0.7 (P < 0.001).

Circulating afamin involved in the T2DM-related complications and its concentration is positively correlated to the miR-122 expression, especially in patient with longstanding diabetes.

The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.

Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary heart disease in comparison to healthy individuals. The downregulation of miR-19a/b has been observed to facilitate the replication of influenza A virus (IAV). miR-19a/b can effectively inhibit IAV replication by targeting and reducing the expression of SOCS1, as observed in cell-based and coronary heart disease mouse models. This mechanism leads to the alleviation of the inhibitory effect of SOCS1 on the interferon (IFN)/JAK/STAT signaling pathway. The results indicate that the IAV employs a unique approach to inhibit the host's type I IFN-mediated antiviral immune responses by decreasing miR-19a/b. These findings provide additional insights into the underlying mechanisms of susceptibility to flu in patients with coronary heart disease. miR-19a/b can be considered as a preventative/therapy strategy for patients with coronary heart disease against influenza virus infection.

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.

Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation.

We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials.

microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.

Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms.

From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1).

Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice.

Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

MicroRNAs (miRNAs) are 19-23 nucleotide long, evolutionarily conserved noncoding RNA molecules that regulate gene expression at the post-transcriptional level. In this review, involvement of miRNAs is summarized in the differentiation and function of immune cells, in anti-infective immune responses, immunodeficiencies and autoimmune diseases. Roles of miRNAs in anticancer immunity and in the transplantation of solid organs and hematopoietic stem cells are also discussed. Major focus is put on the translational clinical applications of miRNAs, including the establishment of noninvasive biomarkers for differential diagnosis and prediction of prognosis. Patient selection and response prediction to biological therapy is one of the most promising fields of application. Replacement or inhibition of miRNAs has enormous therapeutic potential, with constantly expanding possibilities. Although important challenges still await solutions, evaluation of miRNA fingerprints may contribute to an increasingly personalized management of immune dysregulation with a remarkable reduction in toxicity and treatment side effects. More detailed knowledge of the molecular effects of physical exercise and nutrition on the immune system may facilitate self-tailored lifestyle recommendations and advances in prevention.

The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.

MicroRNAs (miR) are small sequence of nucleotides that can affect multiple genes involved in the hepatitis C virus (HCV) life cycle and disease development. The purpose of the present study was to investigate the clinical significance of serum microRNA profiles in a cohort of Egyptian patients with chronic HCV infection before and after combined sofosbuvir and daclatasvir treatment, as well as to gain a better understanding of the exact interaction mechanism in HCV transcriptional activity via differentially expressed miRNAs. For 12 weeks, 50 patients were eligible for and received sofosbuvir (400 mg daily) and daclatasvir (60 mg daily) treatment. Each patient's blood was obtained twice: once before therapy began and again three months afterwards.

The current study found that serum levels of circulating miR-122, miR-221, miR-23a, miR-125, miR-217, miR-224, and miR-181a were high in HCV pre-treatment patients, but after 12 weeks of direct-acting antiviral (DAAs) treatment, there was a statistically significant reduction in expression levels of miR-122, miR-221, miR-23a, miR-125, miR-217, and miR-224 (p < 0.001). There is no statistical significance for miR-181a.

The key differentially expressed microRNAs before and after the direct-acting antiviral (DAA) regimen were connected to the dynamics of chronic HCV infection, suggesting their potential as predictive biomarkers for HCV clearance after sofosbuvir and daclatasvir therapy.

Osteoarthritis (OA) is one of the most common chronic and progressive joint diseases characterized by cartilage degeneration and chondrocyte death. In this study, we aimed to identify the modulation effect of miR-145 on chondrocytes' autophagy during the development of OA.

Osteoarthritis (OA) is one of the most prevalent types of chronic and progressive joint disorder with the symptoms of joint pain and stiffness, and it leads to disability at the end stage. In recent years, microRNA-145 (miR-145) has been found to activate autophagy in various cell types, including mesenchymal stem cells, cardiomyocytes, and osteosarcoma cells. However, it is unknown whether miR-145 regulates the progression of OA by influencing chondrocyte autophagy.

Before investigating the regulatory effect of miR-145 on the autophagic activity of chondrocytes, the expression of miR-145 in human joint samples was analyzed. The targeting relationship between miR-145 and FRS2 was detected by dual luciferase assay. The effect of FRS2 and miR-145 on the autophagic activity of chondrocytes was observed by bidirectional expression of FRS2 and miR-145.

The miR-145 expression and LC3-II/LC3-I ratio were significantly decreased and the SQSTM1 expression was increased in OA patients. The miR-145 overexpression in C20A4 cells increased LC3-II/LC3-I ratio, decreased SQSTM1 expression, and was positively correlated with autophagic activity. Under oxidative stress, miR-145 overexpression significantly improved chondrocyte viability through autophagy stimulation. FRS2 is a potential target of miR-145 via a binding sequence within its 3' UTR. FRS2 acts as the downstream mediator of miR-145 to suppress autophagy through activating PI3K/Akt/mTOR pathways.

The miR-145 acts as a protective factor against chondrocytes by regulating miRFRS2- autophagy axis. The decrease of miR-145 in articular synovial fluid may turn out to be an important marker for early diagnosis of OA, and modulation of miR-145 may represent a promising therapeutic strategy for OA.

Ribonucleic acid (RNA)-based therapies have become an attractive topic in disease intervention, especially with some that have been approved by the FDA such as the mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech, and Spikevax, Moderna) and Patisiran (siRNA-based drug for liver delivery). However, extensive applications are still facing challenges in delivering highly negatively charged RNA to the targeted site. Therapeutic delivery strategies including RNA modifications, RNA conjugates, and RNA polyplexes and delivery platforms such as viral vectors, nanoparticle-based delivery platforms, and hydrogel-based delivery platforms as potential nucleic acid-releasing depots have been developed to enhance their cellular uptake and protect nucleic acid from being degraded by immune systems. Here, we review the growing number of viral vectors, nanoparticles, and hydrogel-based RNA delivery systems; describe RNA loading/release mechanism induced by environmental stimulations including light, heat, pH, or enzyme; discuss their physical or chemical interactions; and summarize the RNA therapeutics release period (temporal) and their target cells/organs (spatial). Finally, we describe current concerns, highlight current challenges and future perspectives of RNA-based delivery systems, and provide some possible research areas that provide opportunities for clinical translation of RNA delivery carriers.

MicroRNAs (miRNAs) are conserved, short, non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They have been implicated in the pathogenesis of cancer and neurological, cardiovascular, and autoimmune diseases. Several recent studies have suggested that miRNAs are key players in regulating the differentiation, maturation, and activation of immune cells, thereby influencing the host immune response to infection. The resultant upregulation or downregulation of miRNAs from infection influences the protein expression of genes responsible for the immune response and can determine the risk of disease progression. Recently, miRNAs have been explored as diagnostic biomarkers and therapeutic targets in various infectious diseases. This review summarizes our current understanding of the role of miRNAs during viral, fungal, bacterial, and parasitic infections from a clinical perspective, including critical functional mechanisms and implications for their potential use as biomarkers and therapeutic targets.

RNA-based therapeutics have the potential to revolutionize the treatment and prevention of human diseases. While early research faced setbacks, it established the basis for breakthroughs in RNA-based drug design that culminated in the extraordinarily fast development of mRNA vaccines to combat the COVID-19 pandemic. We have now reached a pivotal moment where RNA medicines are poised to make a broad impact in the clinic. In this review, we present an overview of different RNA-based strategies to generate novel therapeutics, including antisense and RNAi-based mechanisms, mRNA-based approaches, and CRISPR-Cas-mediated genome editing. Using three rare genetic diseases as examples, we highlight the opportunities, but also the challenges to wide-ranging applications of this class of drugs.

microRNA-122 (miR-122) is a highly conserved microRNA that is predominantly expressed in the liver and plays a critical role in the regulation of liver metabolism. Recent studies have shown that miR-122 is involved in the pathogenesis of various types of cancer, particularly liver cancer. In this sense, The current findings highlighted the potential role of miR-122 in regulating many vital processes in cancer pathophysiology, including apoptosis, signaling pathway, cell metabolism, immune system response, migration, and invasion. These results imply that miR-122, which has been extensively studied for its biological functions and potential therapeutic applications, acts as a tumor suppressor or oncogene in cancer development. We first provide an overview and summary of the physiological function and mode of action of miR-122 in liver cancer. We will examine the various signaling pathways and molecular mechanisms through which miR-122 exerts its effects on cancer cells, including the regulation of oncogenic and tumor suppressor genes, the modulation of cell proliferation and apoptosis, and the regulation of metastasis. Most importantly, we will also discuss the potential diagnostic and therapeutic applications of miR-122 in cancer, including the development of miRNA-based biomarkers for cancer diagnosis and prognosis, and the potential use of miR-122 as a therapeutic target for cancer treatment.

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolytes and acid base. It is associated with poor prognosis and prolonged hospitalization. Therefore, an early diagnosis and treatment to avoid the severe AKI stage are important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for the early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

Hepatitis C virus (HCV) infection causes severe liver diseases and remains a major global public health concern. Current direct-acting antiviral (DAA)-based therapies that target viral proteins involving HCV genome replication are effective, however a minority of patients still fail to cure HCV, rendering a window to develop additional antivirals particularly targeting host functions involving in HCV infection. Here, we utilized the HCV infection cell culture system (HCVcc) to screen in-house compounds bearing host-interacting preferred scaffold for the antiviral activity. Compound HXL-10, a novel fused bicyclic derivative of pyrrolidine and imidazolidinone, was identified as a potent anti-HCV agent with a low cytotoxicity and high specificity. Mechanistic studies showed that HXL-10 neither displayed a virucidal effect nor inhibited HCV genomic RNA replication. Instead, HXL-10 might inhibit HCV assembly by targeting host functions. In summary, we developed a novel anti-HCV agent that may potentially offer additive benefits to the current anti-HCV DDA.

The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host interactions is essential for developing novel antiviral therapies. In this study, we compared the effect of the five members of the microRNA-200 (miR-200) family on IFN-I production during viral infection and found that miR-200b-3p displayed the most pronounced regulatory effect. During viral infection, we discovered that the transcriptional level of microRNA-200b-3p (miR-200b-3p) increased with the infection of influenza virus (IAV) and vesicular stomatitis virus (VSV), and miR-200b-3p production was modulated by the activation of the ERK and p38 pathways. We identified cAMP response element binding protein (CREB) as a novel transcription factor that binds to the miR-200b-3p promoter. MiR-200b-3p reduces NF-κB and IRF3-mediated IFN-I production by targeting the 3' untranslated region (3' UTR) of TBK1 mRNA. Applying miR-200b-3p inhibitor enhances IFN-I production in IAV and VSV-infected mouse models, thus inhibiting viral replication and improving mouse survival ratio. Importantly, in addition to IAV and VSV, miR-200b-3p inhibitors exhibited potent antiviral effects against multiple pathogenic viruses threatening human health worldwide. Overall, our study suggests that miR-200b-3p might be a potential therapeutic target for broad-spectrum antiviral therapy. IMPORTANCE The innate immune response mediated by type I interferon (IFN-I) is essential for controlling viral replication. MicroRNAs (miRNAs) have been found to regulate the IFN signaling pathway. In this study, we describe a novel function of miRNA-200b-3p in negatively regulating IFN-I production during viral infection. miRNA-200b-3p was upregulated by the MAPK pathway activated by IAV and VSV infection. The binding of miRNA-200b-3p to the 3' UTR of TBK1 mRNA reduced IFN-I activation mediated by IRF3 and NF-κB. Application of miR-200b-3p inhibitors exhibited potent antiviral effects against multiple RNA and DNA viruses. These results provide fresh insight into understanding the impact of miRNAs on host-virus interactions and reveal a potential therapeutic target for common antiviral intervention.

Nucleic acid plays a crucial role in countless biological processes. Hence, there is great interest in its detection and analysis in various fields from chemistry, biology, to medicine. Nanoporous crystalline materials exhibit enormous potential as an effective platform for nucleic acid recognition and application. These materials have highly ordered and uniform pore structures, as well as adjustable surface chemistry and pore size, making them good carriers for nucleic acid extraction, detection, and delivery. In this review, the latest developments in nanoporous crystalline materials, including metal organic frameworks (MOFs), covalent organic frameworks (COFs), and supramolecular organic frameworks (SOFs) for nucleic acid recognition and applications are discussed. Different strategies for functionalizing these materials are explored to specifically identify nucleic acid targets. Their applications in selective separation and detection of nucleic acids are highlighted. They can also be used as DNA/RNA sensors, gene delivery agents, host DNAzymes, and in DNA-based computing. Other applications include catalysis, data storage, and biomimetics. The development of novel nanoporous crystalline materials with enhanced biocompatibility has opened up new avenues in the fields of nucleic acid analysis and therapy, paving the way for the development of sensitive, selective, and cost-effective diagnostic and therapeutic tools with widespread applications.

In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many chronic viral infections. We make the point that in several viral infections the lesions can be largely the result of one or more aspects of the host response mediating the cell and tissue damage rather than the virus itself being directly responsible. However, within the reactive inflammatory lesions along with the pro-inflammatory participants there are also other aspects of the host response that may be acting to constrain the activity of the damaging components and are contributing to resolution. This scenario should provide the prospect of rebalancing the contributions of different host responses and hence diminish or even fully control the virus-induced lesions. We identify several aspects of the host reactions that influence the pattern of immune responsiveness and describe approaches that have been used successfully, mainly in model systems, to modulate the activity of damaging participants and which has led to lesion control. We emphasize examples where such therapies are, or could be, translated for practical use in the clinic to control inflammatory lesions caused by viral infections.

Liver fibrosis represents an unmet medical condition with growing incidence and only limited therapeutic options. Interfering with dysregulated gene expression was considered a specific treatment approach, and we are here reviewing the current options to modulate transcription and translation with small molecule inhibitors of involved enzymes, transcription factors or by using non-coding RNA molecules (RNA interference) or DNA antisense oligonucleotides. Despite promising results in preclinical models, only limited data are available from studies in humans.

This expert opinion provides a general overview of how to interfere with gene expression (transcription and translation) and highlighting recent achievements in liver fibrosis.

Many compounds that were explored to modulate gene expression in liver fibrosis (models) were developed as anti-cancer agents. Their use in humans with impaired liver function is often impaired by the lack of specificity to inhibit only fibrosis-related genes in the liver and by associated general toxicity and narrow therapeutic windows. RNAi approaches show a higher degree of specificity and potentially less systemic toxicity. Clinical development in liver fibrosis requires close interaction between pharmaceutical companies and regulatory authorities to address topics like relevant (surrogate) endpoints to achieve meaningful readouts faster.

This study investigated novel tumor suppressor microRNAs (miRNAs) that decrease in plasma and predict chemosensitivity to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC) and revealed their usefulness as novel therapeutic agents. We selected four miRNA candidates (miR-323, 345, 409, and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to NAC and an NCBI database review. Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P = 0.0021, area under the receiver-operating characteristic curve 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P = 0.0710) and were an independent factor predicting a higher response to chemotherapy (P = 0.0022, odds ratio 7.86) and better prognosis (P = 0.0235, hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to cisplatin in mice. Plasma miR-1254 might be a useful biomarker for predicting responses to NAC, and the restoration of plasma miR-1254 levels might improve chemosensitivity in ESCC.

Over the past few decades, humankind has constantly encountered new viral species that create havoc in the socioeconomic balance worldwide. Among the method to combat these novel viral infections, fast and point-of-care diagnosis is of prime importance to contain the spreading of viral infections. However, most sensitive diagnostic systems for viral infections are time-consuming and require well-trained professionals, making it difficult for the patients. In recent years nanozymes emerged as promising therapeutic and fast diagnostic tools due to their multienzyme-like catalytic performance. Nanozymes can be designed using inorganic or organic components with tailorable physicochemical surface properties, enabling the attachment of various molecules and species on the surface of the nanozyme for specific recognition. In addition to the composition, the multienzyme-like catalytic performance can be modulated by the shape and size of the nanoparticles. Due to their multicatalytic abilities, nanozymes can be used for fast diagnosis and therapy for viral infections. Here we attempt to focus on the insights and recent explorations on the advances in designing various types of nanozymes as a theranostic tool for viral infections. Thus, this review intends to generate interest in the clinical translation of nanozymes as a theranostic tool for viral infections by providing knowledge about the multidisciplinary potential of nanozyme. SIGNIFICANCE STATEMENT: The multienzyme-like properties of nanozymes suggest their role in diagnosing and treating various diseases. Although the potential roles of nanozymes for various viral infections have been studied in the last few decades, no review provides recent explorations on designing various types of nanozymes for the detection and treatment of viral infections. This review provides insights into designing nanozymes to diagnose and treat viral infections, assisting future researchers in developing clinically translatable nanozymes to combat novel viral infections.

T-prolymphocytic leukemia (T-PLL) is a rare and mature T-cell malignancy with characteristic chemotherapy-refractory behavior and a poor prognosis. Molecular concepts of disease development have been restricted to protein-coding genes. Recent global microRNA (miR) expression profiles revealed miR-141-3p and miR-200c-3p (miR-141/200c) as two of the highest differentially expressed miRs in T-PLL cells versus healthy donor-derived T cells. Furthermore, miR-141/200c expression separates T-PLL cases into two subgroups with high and low expression, respectively. Evaluating the potential pro-oncogenic function of miR-141/200c deregulation, we discovered accelerated proliferation and reduced stress-induced cell death induction upon stable miR-141/200c overexpression in mature T-cell leukemia/lymphoma lines. We further characterized a miR-141/200c-specific transcriptome involving the altered expression of genes associated with enhanced cell cycle transition, impaired DNA damage responses, and augmented survival signaling pathways. Among those genes, we identified STAT4 as a potential miR-141/200c target. Low STAT4 expression (in the absence of miR-141/200c upregulation) was associated with an immature phenotype of primary T-PLL cells as well as with a shortened overall survival of T-PLL patients. Overall, we demonstrate an aberrant miR-141/200c-STAT4 axis, showing for the first time the potential pathogenetic implications of a miR cluster, as well as of STAT4, in the leukemogenesis of this orphan disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which is commonly known as COVID-19 (COronaVIrus Disease 2019) has creeped into the human population taking tolls of life and causing tremendous economic crisis. It is indeed crucial to gain knowledge about their characteristics and interactions with human host cells. It has been shown that the majority of our genome consists of non-coding RNAs. Non-coding RNAs including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs) display significant roles in regulating gene expression in almost all cancers and viral diseases. It is intriguing that miRNAs and lncRNAs remarkably regulate the function and expression of major immune components of SARS-CoV-2. MiRNAs act via RNA interference mechanism in which they bind to the complementary sequences of the viral RNA strand, inducing the formation of silencing complex that eventually degrades or inhibits the viral RNA and viral protein expression. LncRNAs have been extensively shown to regulate gene expression in cytokine storm and thus emerges as a critical target for COVID-19 treatment. These lncRNAs also act as competing endogenous RNAs (ceRNAs) by sponging miRNAs and thus affecting the expression of downstream targets during SARS-CoV-2 infection. In this review, we extensively discuss the role of miRNAs and lncRNAs, describe their mechanism of action and their different interacting human targets cells during SARS-CoV-2 infection. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new therapies against SARS-CoV-2.