Search Results (166)

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that causes progressive renal failure, nephrolithiasis, and nephrocalcinosis in children. It is characterized by hepatic overproduction of oxalate. Conventional management, which involves combined liver–kidney transplantation, vitamin B6 supplementation, and intense hydration, does not address the underlying metabolic defect for most patients and it generally provides only supportive care. The first approved disease-modifying treatment for pediatric PH1 is Lumasiran, a small interfering RNA (siRNA) therapeutic. By specifically inhibiting the hepatic glycolate oxidase mRNA, Lumasiran lowers the production of oxalate at its origin. Along with fewer kidney stone events and stabilization of nephrocalcinosis, clinical trials (ILLUMINATE-A/B/C) showed significant decreases in urinary oxalate excretion. The most frequently reported adverse event is mild injection-site reactions, which are generally well tolerated. The molecular mechanism, pharmacokinetics, and clinical effectiveness of Lumasiran in children with PH1 are compiled in this review. We go over possible long-term safety concerns, the impact of early intervention on renal outcomes, and the function of siRNA therapies in pediatric precision medicine. Furthermore, we highlight Lumasiran’s importance as a model for targeted treatment in uncommon pediatric kidney diseases by considering it in the larger context of RNAi-based therapies. A paradigm shift in pediatric nephrology is signaled by Lumasiran, which changes the therapeutic approach from supportive care to precision, targeted medicine. Further research and empirical data will clarify its long-term advantages, the best ways to treat it, and the possible use of siRNA technologies for other genetic renal disorders. Full article

RNA interference (RNAi) holds promise as a gene-silencing therapy for liver cancer but faces challenges related to siRNA instability, short half-life, and inefficient cellular uptake. In this study, we designed a self-assembling RNA nanoparticle targeting three oncogenes—hTERT, BIRC5, and FGFR1—key drivers of cancer progression. These RNA nanoparticles demonstrated enhanced stability and specificity, eliminating the need for conventional toxic delivery carriers. Functional assays revealed that the nanoparticles effectively suppressed the proliferation, migration, tumor growth and apoptosis of a Hepatocellular carcinoma cell line, Hep3B. The nanoparticles exhibited excellent safety and efficacy in xenograft model mice, without off-target toxicity. This work introduces a scalable, biocompatible RNA nanoparticle platform with multi-targeting capability, paving the way for improved RNAi-based therapeutics. Our findings offer a promising strategy for advancing personalized cancer therapies and underscore the broader potential of RNA nanotechnology in addressing complex malignancies. Full article

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative dis-ease caused by the expansion of cytosine–adenine–guanine (CAG) repeats in the ataxin-1 (ATXN1) gene, leading to toxic gain-of-function of the ataxin-1 (ATXN1) protein. This narrative review systematizes the clinical and genetic aspects of SCA1 and discusses key molecular and cellular mechanisms: the ATXN1-CIC ataxin-1-Capicua complex (ATXN1-CIC), the role of serine 776 (Ser776) phosphorylation, interactions with 14-3-3 proteins, transcriptional dysregulation, and critically analyzes experimental models of the disease in vivo and in vitro. In addition, it presents a descriptive quantitative analysis of the literature on in vivo SCA1 models, conducted using a defined search methodology with a cut-off date of 23 November 2025. For each model, phenotypic markers, molecular signatures, and applicability to preclinical testing tasks are summarized. A comparison of the models reveals their complementarity and outlines optimal research trajectories, including omics approaches and prospects for targeted antisense oligonucleotide (ASO) therapy, RNA interference (RNAi), and genome editing. The result is a practical guide for selecting a model in accordance with specific hypotheses and translational objectives. Full article

Small interfering RNAs (siRNAs) have emerged as a powerful tool in the treatment of aggressive cancers. By exploiting and mimicking the natural gene regulation mechanism of RNA interference (RNAi), they allow for sequence-specific silencing of aberrant genes. siRNA-mediated knockdown of the inflammatory cytokine tumour necrosis factor-alpha (TNF-α) presents a novel therapy for triple-negative breast cancer (TNBC). This study investigated the potential of novel biomimetic glutathione-synthesised gold nanoclusters (AuNCs) as siRNA delivery vehicles. AuNCs were functionalized with biocompatible chitosan and polyethene glycol, and their interactions with siRNAs were investigated through binding studies. In vitro cytotoxicity and cellular uptake were conducted in the human breast cancer (MCF-7), TNBC (MDA-MB-231), and embryonic kidney (HEK293) cells, while the effect of anti-TNF-α siRNA nanocomplexes on biological processes, such as oxidative stress, apoptosis, and cell cycle distribution, was investigated using flow cytometry. UV–visible and Fourier transform infrared spectroscopy, as well as transmission electron microscopy, confirmed the synthesis and functionalization of the AuNCs. Functionalized AuNCs (FAuNC) effectively bound and condensed siRNA and protected against nuclease degradation. AuNCs facilitated efficient cellular uptake and were well-tolerated in vitro. Anti-TNF-α siRNA treatment of the MDA-MB-231 cells increased apoptosis and oxidative stress levels, and affected cell cycle distribution. Although the overall knockdown was low, these FAuNCs exhibited favorable physicochemical characteristics, low cytotoxicity and good cellular uptake in vitro, warranting further optimisation for improved delivery of therapeutic siRNAs. Full article

Background: Hepatocellular carcinoma (HCC) remains a major global health challenge with limited therapeutic options. Although RNA interference (RNAi) enables precise gene silencing, its clinical application is restricted by siRNA instability, inefficient cellular uptake, and the requirement for potentially toxic delivery carriers. To address these limitations, a dual-targeted branched siRNA nanostructure (GT-multi-siRNA) was developed to simultaneously silence two HCC-related oncogenes, GP73 and hTERT. Methods: GT-multi-siRNA was synthesized in Escherichia coli and characterized for particle size, stability, Dicer processing efficiency, intracellular retention, and cytotoxicity. Its therapeutic effects were evaluated through gene-silencing assays, proliferation and migration assays in Hep3B cells, and intratumoral administration in a xenograft mouse model. Histopathology and cytokine profiling were conducted to assess biosafety. Results: GT-multi-siRNA formed uniform nanoparticles (50–100 nm) with moderate physicochemical stability and minimal cytotoxicity at concentrations ≤ 200 ng/μL. The nanostructure was efficiently processed by Dicer into functional siRNAs and remained detectable intracellularly for at least 36 h. In Hep3B cells, GT-multi-siRNA reduced GP73 and hTERT mRNA and protein levels by approximately 50%, accompanied by significant inhibition of cell proliferation and migration. In vivo, a single intratumoral dose suppressed tumor growth, while a two-dose regimen markedly limited tumor progression. No liver toxicity was observed, and cytokine analysis showed selective IL-4 upregulation without influencing IL-6 levels. Conclusions: GT-multi-siRNA demonstrates potent dual-gene silencing activity and favorable biosafety, providing a promising RNAi-based therapeutic strategy for targeted HCC treatment. Full article

Background: Osteoporosis is one of the most common bone metabolic diseases that affects mainly the health of elderly people. It is a kind of prevalent chronic disease, and the conventional treatment methods have some limitations or side effects. Targeting nanoparticles represent a novel technology that has garnered extensive attention in recent years. They can selectively enhance the drug concentration at the targeted site, offering a novel treatment method. Methods: The review is carried out according to the Preferred Reporting Items for Systematic Reviews (PRISMA 2020) guidelines. Results: This article comprehensively summarizes recent research progress on the status of existing anti-osteoporosis drugs and bone-targeting nanoparticles for the treatment of osteoporosis, including their carrier materials, modification techniques, preparation methods, and function mechanisms. It also discusses their applications in RNA interference (RNAi) therapy and other related areas. Furthermore, given the limitations of bone-targeting nanoparticles, solutions and viewpoints have been proposed. This review summarizes that bone-targeting nanoparticles are useful for osteoporosis therapy and provide a novel perspective for new drug discovery. Conclusions: Bone-targeting nanoparticles overcome the limitations of traditional treatment methods and enhance therapeutic efficacy. However, the clinical translation of bone-targeted nanoparticles remains challenging and requires further investigation. Full article

RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, tune biodistribution, and enable organ- and cell-selective delivery. We highlight design levers that now define the field: ligand-guided targeting, stimuli-responsive release, biomimicry and endogenous carriers, and rational co-delivery with small molecules. Across major disease areas—cancer and cardiovascular, respiratory, and urological disorders—these platforms achieve tissue-selective uptake (e.g., macrophages, endothelium, and myocardium), traverse physiological barriers (including the blood–brain barrier and fibrotic stroma), and remodel hostile microenvironments or immune programs to enhance efficacy while maintaining favorable safety profiles. Early clinical studies reflect this diversity, spanning targeted nanoparticles, local drug depots, exosome and cellular carriers, and inhaled formulations, e.g., and converge on core phase-I endpoints (safety, maximum tolerated dose, pharmacokinetics/pharmacodynamics, and early activity). Looking ahead, priorities include good manufacturing practice scale, consistent manufacture—especially for EVs; more efficient loading and cargo control; improved endosomal escape and biodistribution; and rigorous, long-term safety evaluation with standardized, head-to-head benchmarking. Emerging directions such as in vivo EVs biogenesis, theragnostic integration, and data-driven formulation discovery are poised to accelerate translation. Collectively, nanoparticle-enabled RNAi has matured into a versatile, clinically relevant toolkit for precise gene silencing, positioning the field to deliver next-generation therapies across diverse indications. Full article

Endometriosis is a common gynecological condition that affects fertility in many women of reproductive age worldwide. This multifaceted disease exhibits a pathogenesis characterized by hormonal and immune system dysregulations, alongside increased angiogenic activity within the peritoneum. The aberrant proliferation of endometrial tissue outside the uterus is associated with vascularization in ectopic endometriotic lesions. Consequently, RNA interference (RNAi)-based angiogenic therapies targeting the VEGFA gene present a promising strategy for the treatment of endometriosis. To ensure the efficacy of RNAi-based therapy, it is critical to develop carriers capable of precisely delivering small interfering RNA (siRNA) to target cells. Additionally, the instability of polyplexes in vivo must be regarded as a pivotal aspect influencing the success of non-viral delivery. In this study, we introduce ternary polyplexes comprising siRNA and a carrier derived from an arginine–histidine-rich peptide, which is further coated with a glutamate–histidine-rich polymer modified using an SDF-1 chemokine-derived ligand for targeting CXCR4-expressing cells. The physicochemical characteristics of the siRNA-polyplexes, along with cellular toxicity and GFP gene silencing efficacy, were assessed in vitro. The anti-angiogenic potential of anti-VEGFA siRNA-polyplexes was evaluated by measuring the size of endometrial lesions, conducting immunohistochemical staining, and analyzing VEGFA gene expression. For in vivo experiment, a rat model of endometriosis induced by subcutaneous auto-transplantation of uterine tissue was utilized. A significant reduction in the growth of endometriotic implants and silencing of VEGFA gene expression was observed when compared to the saline-treated control group. The results of this study strongly suggest that the developed ternary polyplexes have significant potential as an efficient tool for the development of anti-angiogenic RNAi-based therapies for endometriosis. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive tumor biology, poor vascularization, dense stromal barriers, and profound resistance to chemotherapy. GAIP-interacting protein C-terminus 1 (GIPC1), a PDZ-domain-containing adaptor protein, is highly overexpressed in PDAC and plays a critical role in tumor progression and chemoresistance. This study aimed to develop and evaluate a novel tumor-targeted liposomal siRNA delivery system (LGIPCsi) to silence GIPC1 and enhance the therapeutic efficacy of gemcitabine (GEM) in PDAC; Methods: LGIPCsi nanoparticles were synthesized and optimized for physicochemical stability, siRNA complexation efficiency, and tumor-targeting capability. Their therapeutic efficacy was assessed using in vitro pancreatic cancer cell models and in vivo orthotopic and patient-derived xenograft (PDX) models of PDAC. Biodistribution, tumor uptake, and antitumor efficacy were evaluated following systemic administration. Combination studies were performed to assess the synergistic effects of LGIPCsi and GEM; Results: GIPC1 silencing significantly sensitized pancreatic cancer cells to GEM, resulting in enhanced inhibition of tumor cell proliferation in vitro. In vivo, systemic administration of LGIPCsi achieved efficient intratumoral delivery of siGIPC1, leading to marked tumor growth suppression. Combination therapy with GEM and LGIPCsi produced synergistic antitumor effects, with substantial tumor regression compared to monotherapy groups. Importantly, no significant systemic toxicity was observed in treated animals; Conclusions: This study identifies GIPC1 as a promising therapeutic target in PDAC and demonstrates that tumor-targeted siRNA nanomedicine can effectively overcome chemoresistance when combined with standard chemotherapy. The LGIPCsi platform offers a rational and translational strategy to enhance treatment efficacy in PDAC through targeted RNAi-based combination therapy. Full article

Spinal cord injury (SCI) is a neurological condition often resulting in permanent motor and sensory deficits, for which effective treatments remain limited. RNA interference (RNAi) is a post-transcriptional mechanism of the downregulation of gene expression mediated by small interfering RNAs. RNAi has demonstrated therapeutic efficacy in various neurological disorders, positioning it as a promising yet underexplored therapeutic strategy for SCI. Here, we provide a focused overview of the key pathological processes in SCI, including primary mechanical injury and secondary cascades such as inflammation, mitochondrial dysfunction, excitotoxicity, oxidative stress, multiple forms of cell death, and others. The potential of RNAi to selectively silence genes implicated in these pathological processes, thereby enhancing neuroprotection and functional recovery, is highlighted. We point out that not only protein-coding genes, but non-coding RNAs (ncRNAs) are suitable targets for RNAi. Novel RNAi tools such as CRISPR-Cas13 might revolutionize the field and offer new opportunities for SCI therapy. However, despite all these promising findings, relevant translational studies of RNAi remain scarce. Challenges related to delivery methods, long-term efficacy, and cell-specific targeting must be addressed. Importantly, combining RNAi with other strategies such as cell- or biomaterial-based therapies may enhance therapeutic outcomes. Future investigations should prioritize systematic comparisons of RNAi targets and delivery systems, ideally at single-cell resolution and in different SCI models, to identify the most relevant molecular pathways for clinical translation. Overall, RNAi represents a compelling but still underdeveloped approach for SCI therapy, requiring continued refinement to reach clinical application. Full article

RNA interference (RNAi) is a powerful mechanism of post-transcriptional gene regulation in which small interfering RNA (siRNA) is utilized to target and degrade specific RNA sequences. In this study, experiments were conducted to evaluate the efficacy of combination siRNA therapy against enterovirus 71 (EV71) and the potential of this therapy to delay or prevent the emergence of resistance in vitro. siRNAs targeting multiple genes of EV71 were designed, and the effects of a cocktail of siRNAs on viral replication were assessed compared to those of single-siRNA treatment. Cotransfection of multiple siRNAs targeting different protein-coding genes of the EV71 genome effectively suppressed escape mutants resistant to RNAi. Combination therapy with siRNAs targeting multiple viral genes successfully prevented viral escape mutations over five passages. By contrast, serial passaging with a single siRNA led to the rapid emergence of resistance, with mutations identified in the siRNA target sites. The combination of siRNAs specifically targeting different regions demonstrated an additive effect and was more effective than individual siRNAs at inhibiting EV71 replication. This study supports the effectiveness of combination therapy using siRNAs targeting multiple genes of EV71 to inhibit viral replication and prevent the emergence of resistant escape mutants. Overall, the findings identify RNAi targeting multiple viral genes as a potential strategy for therapeutic development against viral diseases and for preventing the emergence of escape mutants resistant to antiviral RNAi. Full article

Cucumber green mottle mosaic virus (CGMMV) represents a serious threat in the production of watermelon. Small RNAs facilitate a mechanism known as RNA interference (RNAi), which regulates gene expression. RNAi technology employs foreign double-stranded RNAs (dsRNAs) to target and reduce the expression levels of specific genes in plants by interfering with their mRNAs. In this study, watermelon plants were treated with dsRNAs of CGMMV MET, IR, and HEL fragments that had been generated in E. coli HT115. We investigated variations in several factors, including viral accumulation, virus-derived small interfering RNAs (vsiRNAs), and symptom severity. MET-dsRNA, IR-dsRNA and HEL-dsRNA dramatically decreased the symptoms of CGMMV in plants in the growth chamber test. Plants treated with viral-derived dsRNA showed a considerable decrease in both virus titers and vsiRNA levels. We also explored the mobility of spray-on dsRNA-derived long dsRNA and discovered that it could be identified in both inoculated leaves and the systemic leaves. IR-dsRNA outperformed MET-dsRNA and HEL-dsRNA in dsRNA therapy. Illumina sequencing of small RNAs from watermelon plants treated with IR-dsRNA and those that were not treated showed that the decreased accumulation of vsiRNAs was consistent with interference with CGMMV infection in systemic leaves. dsRNA-treated plants showed a higher level of 24-nt viral siRNA and lower level of 22-nt viral siRNA accumulation, while 22-nt viral siRNA predominated in untreated plants, indicating that dsRNA treatment improved DCL3 activity. In conclusion, our research provides deeper insights into the mechanism of antiviral RNA interference and confirms the effectiveness of applying dsRNA locally to enhance plant antiviral activity. Full article

Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen that infects many animals with mild symptoms. However, swine is the most receptive host and causes acute and lethal myocarditis and/or encephalitis, and induces sudden death in piglets. There are currently no approved antivirals against EMCV. In recent years, antiviral therapies based on small interfering RNA (siRNA) have been rapidly developed as effective alternative therapies. In this study, we designed siRNAs targeting highly conserved regions in the EMCV genome coinciding with VP2 and 3C genes. We show that these siRNAs were non-immunostimulatory and significantly inhibited EMCV replication in vitro. The siRNAs were then complexed in liposomes before testing in a lethal EMCV mouse model in vivo. Both prophylactic and therapeutic intravenous delivery of siRNAs ameliorated viral infection in multiple organs and improved animal survival. This is the first demonstration of the use of a liposomal delivery platform to deliver highly conserved anti-EMCV siRNAs for EMCV antiviral therapy in vivo. Full article

Endometriosis is a chronic estrogen-dependent condition with limited treatment options, often requiring surgery and long-term hormonal therapy that may impair ovarian function. Despite advancements in gene therapy for other diseases, its application in endometriosis remains largely unexplored. This study aimed to evaluate the potential of adeno-associated virus (AAV) vectors for targeted gene therapy in endometriosis. We screened multiple AAV serotypes for infectivity in primary human ectopic and eutopic endometrial cells as well as normal ovarian stromal cells. AAV serotype 3 (AAV3) demonstrated selective infectivity toward endometrial cells while sparing ovarian tissue. AAV3-mediated delivery of small interfering RNA targeting estrogen receptor 2 reduced Estrogen receptor beta (ERβ) expression to 27% in ectopic and 49% in eutopic cells. Under estradiol and inflammatory stimulation, ERβ knockdown led to modest reductions in cellular metabolic activity in eutopic cells, whereas effects in ectopic cells did not reach statistical significance. Dual targeting of ERβ and prostaglandin-endoperoxide synthase 2 (PTGS2) showed numerically lower metabolic activity than controls under some conditions but without consistent statistical significances. These findings suggest that AAV3 can serve as an ovary-sparing, endometriosis-specific vector that facilitates gene silencing while yielding limited phenotypic effects. This gene delivery system may provide a basis for developing future gene-based therapies for endometriosis. Full article

RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems—with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates—and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology. Full article