ABSTRACT
The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are nanotechnology-based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next-generation multiepitope nanovaccines co-deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD-L1 expression. As a case study, we focused on SARS-CoV-2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular- and humoral-specific responses against SARS-CoV-2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS-CoV-2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology-based vaccines, it is shown that the lyophilized nanovaccine is stable for long-term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats.
ABSTRACT
Spherical nucleic acids (SNAs) are nanostructures with the DNA arranged radially on the surface, thus allowing specific binding with cancer cells expressing high levels of scavenger receptor-A to enhance cellular uptake. However, conventional carriers for SNAs are cytotoxic, not degradable and difficult to deliver multiple payloads. In this study, we developed charge-reversible coordination-crosslinked SNAs to deliver dual anti-cancer genes and ferroptosis payload for anti-cancer purposes. To this end, we modified poly(lactic acid) (PLA) with functionalized side chains to allow its binding with antisense oligonucleotides (ASOs) and siRNA, annealed two single-stranded RNAs to obtain double-stranded RNA, and introduced a polyethylene glycol (PEG) shell to enhance the circulation time. Additionally, the ferroptosis payload imidazole was coordinated with iron ions as a core-crosslinked group to enhance the stability of SNAs and efficiency to kill cancer cells. We demonstrated that this novel nanocomplex efficiently internalized and killed CT-26 cells in vitro. In vivo data confirmed that the dual gene delivery system successfully targeted CT-26 tumors in tumor-bearing BALB/c mice, and exhibited strong tumor suppression ability, without inducing adverse toxic effects. Taken together, our dual gene therapy system offered an enhanced anti-tumor solution by simultaneously delivering dual anti-cancer genes and ferroptosis payload in tumor microenvironment.
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Viral suppressor RNA silencing (VSR) is essential for successful infection. Nucleotide-binding and leucine-rich repeat (NLR)-based and autophagy-mediated immune responses have been reported to target VSR as counter-defense strategies. Here, we report a protein arginine methyltransferase 6 (PRMT6)-mediated defense mechanism targeting VSR. The knockout and overexpression of PRMT6 in tomato plants lead to enhanced and reduced disease symptoms, respectively, during tomato bush stunt virus (TBSV) infection. PRMT6 interacts with and inhibits the VSR function of TBSV P19 by methylating its key arginine residues R43 and R115, thereby reducing its dimerization and small RNA-binding activities. Analysis of the natural tomato population reveals that two major alleles associated with high and low levels of PRMT6 expression are significantly associated with high and low levels of viral resistance, respectively. Our study establishes PRMT6-mediated arginine methylation of VSR as a mechanism of plant immunity against viruses.
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The hepatitis B virus (HBV) infects many people worldwide. As HBV infection frequently leads to liver fibrosis and carcinogenesis, developing anti-HBV therapeutic drugs is urgent. Therapeutic drugs for preventing covalently closed circular DNA (cccDNA) production, which can eliminate HBV infection, are unavailable. The host factor dedicator of cytokinesis 11 (DOCK11) is involved in the synthesis and maintenance of HBV cccDNA in vitro. However, the effectiveness of DOCK11 as a target for the in vivo elimination of HBV cccDNA remains unclear. In this study, we assess whether DOCK11 inhibitors suppress HBV cccDNA production in mouse models of HBV infection. The tocopherol-conjugate hetero- gapmer, a DNA/RNA duplex of gapmer/complementary RNA targeting the DOCK11 sequence, partially reduces the expression of DOCK11, but not that of HBV cccDNA, in the livers of HBV-infected human hepatocyte chimeric mice, along with weight loss and decreased serum human albumin levels. Lipid nanoparticle-encapsulated chemically modified siRNAs specific for DOCK11 suppress DOCK11 expression and decrease HBV cccDNA levels without adverse effects in the mice. Therefore, nucleic acid-based drugs targeting DOCK11 in hepatocytes are potentially effective anti-HBV therapeutics that can reduce HBV cccDNA levels in vivo.
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Introduction: Dysregulated calcium homeostasis and consequentially aberrant Ca2+ signalling could enhance survival, proliferation and metastasis in various cancers. Despite rapid development in exploring the ion channel functions in relation to cancer, most of the mechanisms accounting for the impact of ion channel modulators have yet to be fully clarified. Although harnessing small interfering RNA (siRNA) to specifically silence gene expression has the potential to be a pivotal approach, its success in therapeutic intervention is dependent on an efficient delivery system. Nanoparticles have the capacity to strongly bind siRNAs. They remain in the circulation and eventually deliver the siRNA payload to the target organ. Afterward, they interact with the cell surface and enter the cell via endocytosis. Finally, they help escape the endo-lysosomal degradation system prior to unload the siRNAs into cytosol. Carbonate apatite (CA) nanocrystals primarily is composed of Ca2+, carbonate and phosphate. CA possesses both anion and cation binding domains to target negatively charged siRNA molecules. Methods: Hybrid CA was synthesized by complexing CA NPs with a hydrophilic polysaccharide - hyaluronic acid (HA). The average diameter of the composite particles was determined using Zetasizer and FE-SEM and their zeta potential values were also measured. Results and Discussion: The stronger binding affinity and cellular uptake of a fluorescent siRNA were observed for HA-CA NPs as compared to plain CA NPs. Hybrid CA was electrostatically bound individually and combined with three different siRNAs to silence expression of calcium ion channel and transporter genes, TRPC6, TRPM8 and SLC41A1 in a human breast cancer cell line (MCF-7) and evaluate their potential for treating breast cancer. Hybrid NPs carrying TRPC6, TRPM8 and SLC41A1 siRNAs could significantly enhance cytotoxicity both in vitro and in vivo. The resultant composite CA influenced biodistribution of the delivered siRNA, facilitating reduced off target distribution and enhanced breast tumor targetability.
Subject(s)
Apatites , Breast Neoplasms , Hyaluronic Acid , Nanoparticles , RNA, Small Interfering , Humans , Apatites/chemistry , Apatites/pharmacology , RNA, Small Interfering/chemistry , RNA, Small Interfering/pharmacokinetics , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/pharmacology , RNA, Small Interfering/genetics , Hyaluronic Acid/chemistry , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Nanoparticles/chemistry , Female , Animals , Cell Survival/drug effects , Cell Line, Tumor , MCF-7 Cells , Cell Proliferation/drug effects , MiceABSTRACT
Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120â¯nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72â¯h showed cell viability above 80â¯% at concentrations up to 8.5â¯×â¯101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5⯵M and above (pâ¯<â¯0.05) after 24â¯h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50â¯%. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37â¯% reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.
ABSTRACT
Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.
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Cancers are increasing in prevalence and many challenges remain for their treatment, such as chemoresistance and toxicity. In this context, siRNA-based therapeutics have many potential advantages for cancer therapies as a result of their ability to reduce or prevent expression of specific cancer-related genes. However, the direct delivery of naked siRNA is hindered by issues like enzymatic degradation, insufficient cellular uptake, and poor pharmacokinetics. Hence, the discovery of a safe and efficient delivery vehicle is essential. This review explores various lipid and polymer-based delivery systems for siRNA in cancer treatment. Both polymers and lipids have garnered considerable attention as carriers for siRNA delivery. While all of these systems protect siRNA and enhance transfection efficacy, each exhibits its unique strengths. Lipid-based delivery systems, for instance, demonstrate high entrapment efficacy and utilize cost-effective materials. Conversely, polymeric-based delivery systems offer advantages through chemical modifications. Nonetheless, certain drawbacks still limit their usage. To address these limitations, combining different materials in formulations (lipid, polymer, or targeting agent) could enhance pharmaceutical properties, boost transfection efficacy, and reduce side effects. Furthermore, co-delivery of siRNA with other therapeutic agents presents a promising strategy to overcome cancer resistance. Lipid-based delivery systems have been demonstrated to encapsulate many therapeutic agents and with high efficiency, but most are limited in terms of the functionalities they display. In contrast, polymeric-based delivery systems can be chemically modified by a wide variety of routes to include multiple components, such as release or targeting elements, from the same materials backbone. Accordingly, by incorporating multiple materials such as lipids, polymers, and/or targeting agents in RNA formulations it is possible to improve the pharmaceutical properties and therapeutic efficacy while reducing side effects. This review focuses on strategies to improve siRNA cancer treatments and discusses future prospects in this important field.
ABSTRACT
Extracellular vesicles (EVs) act as mediators for intercellular transfer of Aß and tau proteins, promoting the propagation of these pathological misfolded proteins throughout the brain in Alzheimer's disease (AD). Levels of blood exosomal Aß42, total Tau (t-Tau) and phosphorylated Tau (p-Tau) had a high correlation with their concentrations in cerebrospinal fluid (CSF), demonstrating that exosomal biomarkers have equal contribution as those in CSF for the diagnosis of AD. We aimed to comprehensively characterize the proteome of plasma-derived EVs to identify differentially expressed proteins (DEPs) and pathways in AD. Tandem mass tag (TMT) labeled quantitative proteomics was applied to analyze plasma-derived EV proteins in 9â¯CE patients and 9 healthy controls. 335 proteins were quantified, and 12 DEPs were identified including seven upregulated proteins and five down-regulated proteins. Oligomerized Aß1-42 induced SH-SY5Y cell damage model was built to mimic the pathological changes of AD, and small interfering RNA (siRNA) against S100A8 was used to knock down S100A8 expression. Results displayed S100A8 was down regulated in plasma-derived EVs from AD patients, while enriched in EVs derived from Aß1-42-induced SH-SY5Y cells. Furthermore, Aß1-42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aß levels in cell lysate and EVs, especially in EVs. SIGNIFICANCE: The investigation aimed to comprehensively characterize the proteome of plasma-derived EVs to identify DEPs and potential biomarker of AD. S100A8 was found down regulated in plasma-derived EVs from AD patients using TMT labeled quantitative proteomics. The diagnostic value of S100A8 was also confirmed using receiver operating characteristic curve (ROC) analysis. Furthermore, Aß1-42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aß levels in cell lysate and EVs, especially in EVs. The preliminary findings suggest that suppression of S100A8 expression inhibits Aß aggregation both in cell lysate and EVs from Aß1-42-induced SH-SY5Y cells, and S100A8 more likely regulates Aß aggregation via EVs. Therefore, plasma-derived EV S100A8 might be a potential biomarker of AD. Manipulation of S100A8 expression may be a novel therapeutic strategy in the treatment of AD.
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The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1ß, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses.
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RNA-dependent RNA Polymerases (RdRPs) synthesize double-stranded RNA (dsRNA) from a single-stranded RNA (ssRNA) template. In plants, dsRNAs produced by RdRPs can be further processed into small interfering RNA (siRNAs) with different lengths, ranging from 21 to 24 nucleotides (nt). These siRNAs play a pivotal role in various biological processes, including antiviral responses, transposable elements silencing, DNA methylation, and the regulation of plant reproduction and development. Recent research has reported significant progress in uncovering the molecular mechanisms of plant RNA-DEPENDENT RNA POLYMERASE 2 (RDR2), a representative RdRP involved in the RNA-directed DNA methylation (RdDM) pathway. These discoveries provide a molecular basis underlying the principles of RdRP function and offer insights into potential advancements in crop breeding and antiviral defense strategies.
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Background: Drug resistance is common in triple-negative breast cancer (TNBC) therapy. To identify a method to overcome chemotherapy resistance in TNBC cells, an siRNA targeting the AXL gene (siAXL), which can overcome drug resistance, was used in this study. A nanodelivery system was constructed to co-deliver siAXL and paclitaxel (PTX). Methods: A biodegradable and tumor microenvironment (TME)-sensitive mPEG-coated dendritic polylysine material (PDPLL) was synthesized. This material was used to construct single-molecule nanoparticles to co-deliver PTX and siAXL. The drug encapsulation and morphological properties of the nanoparticles (NPs) were characterized. The sensitivity of the NPs to the TME was evaluated in vitro with a dialysis method. The tumor-targeting effect of the PDPLL NPs was evaluated by fluorescence imaging and drug distribution evaluation in vivo. The ability to overcome drug resistance was evaluated using PTX-resistant 4T1 cells (4T1/PTX cells) in both in vitro and in vivo models. Results: PDPLL NPs had a particle size of 49.6 ± 5.9 nm and a zeta potential of 7.87 ± 0.68 mV. The PTX drug loading (DL)% was 2.59%. The siAXL DL was 2.5 mg PDPLL: 10 nmol siAXL. The release of PTX showed sustained release performance. The release of siAXL showed sensitivity for the TME. The NPs were stable in the plasma. The NPs promoted cell uptake by PTX-resistant 4T1 cells (4T1/PTX) and promoted tumor targeting and permeability in vivo. siAXL enhanced the toxicity and apoptosis efficiency of PTX in 4T1/PTX cells, as well as the cycle arrest efficiency caused by PTX. The NPs improved the above effects. In mouse 4T1/PTX orthotopic tumors, the NPs enhanced the sensitization of PTX to siAXL. Conclusion: The PDPLL NP co-delivery system possesses good encapsulating potential not only for PTX but also for siRNA. It can enhance the tumor-targeting effect and overcome the drug resistance of 4T1/PTX both in vitro and in vivo. This system is a potential delivery system for RNAs.
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A series of successes in RNA interference (RNAi) therapies for liver diseases using lipid nanoparticles and N-acetylgalactosamine have heralded a current era of RNA therapeutics. However, alternative delivery strategies are required to take RNAi out of the comfort zone of hepatocytes. Here we report SIRPα IgV/anti-CD47 siRNA (vS-siCD47) conjugates that selectively and persistently disrupt the antiphagocytic CD47/SIRPα axis in solid tumors. Conjugation of the SIRPα IgV domain protein to siRNAs enables tumor dash through CD47-mediated erythrocyte piggyback, primarily blocking the physical interaction between CD47 on cancer cells and SIRPα on phagocytes. After internalization of the vS-siCD47 conjugates within cancer cells, the detached free-standing anti-CD47 siRNAs subsequently attack CD47 through the RNAi mechanism. The dual-action approach of the vS-siCD47 conjugate effectively overcomes the "don't eat me" barrier and stimulates phagocyte-mediated tumor destruction, demonstrating a highly selective and potent CD47-blocking immunotherapy. This delivery strategy, employing IgV domain protein-siRNA conjugates with a dual mode of target suppression, holds promise for expanding RNAi applications beyond hepatocytes and advancing RNAi-based cancer immunotherapies for solid tumors.
Subject(s)
CD47 Antigen , RNA, Small Interfering , Receptors, Immunologic , CD47 Antigen/metabolism , CD47 Antigen/chemistry , Humans , RNA, Small Interfering/chemistry , Animals , Mice , Receptors, Immunologic/metabolism , Neoplasms/therapy , Neoplasms/genetics , Neoplasms/pathology , Antigens, Differentiation , Cell Line, TumorABSTRACT
Pyroptosis is an inflammatory programed cell death process that plays a crucial role in cancer therapeutic, while Gasdermin-D is a critical effector protein for pyroptosis execution. This review discusses the intricate interactions between Gasdermin-D and some non-coding RNAs (lncRNA, miRNA, siRNA) and their potential application in the regulation of pyroptosis as an anticancer therapy. Correspondingly, these ncRNAs significantly implicate in Gasdermin-D expression and function regarding the pyroptosis pathway. Functioning as competing endogenous RNAs (ceRNAs), these ncRNAs might regulate Gasdermin-D at the molecular level, underlying fatal cell death caused by cancer and tumor propagation. Therefore, these interactions appeal to therapeutics, offering new avenues for cancer treatment. It address this research gap by discussing the possible roles of ncRNAs as mediators of gasdermin-D regulation. It suggest therapeutic strategies based on the current research findings to ensure the interchange between the ideal pyroptosis and cancer cell death.
Subject(s)
Intracellular Signaling Peptides and Proteins , Neoplasms , Phosphate-Binding Proteins , Pyroptosis , RNA, Untranslated , Pyroptosis/physiology , Humans , Neoplasms/pathology , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/therapy , Phosphate-Binding Proteins/metabolism , Phosphate-Binding Proteins/genetics , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Animals , Gene Expression Regulation, Neoplastic , GasderminsABSTRACT
Lin28A and Lin28B are paralogous RNA-binding proteins that play fundamental roles in development and cancer by regulating the microRNA family of tumor suppressor Let-7. Although Lin28A and Lin28B share some functional similarities with Let-7 inhibitors, they also have distinct expression patterns and biological functions. Increasing evidence indicates that Lin28A and Lin28B differentially impact cancer stem cell properties, epithelial-mesenchymal transition, metabolic reprogramming, and other hallmarks of cancer. Therefore, it is important to understand the overexpression of Lin28A and Lin28B paralogs in specific cancer contexts. In this review, we summarize the main similarities and differences between Lin28A and Lin28B, their implications in different cellular processes, and their role in different types of cancer. In addition, we provide evidence of other specific targets of each lin28 paralog, as well as the lncRNAs and miRNAs that promote or inhibit its expression, and how this impacts cancer development and progression.
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BACKGROUND: Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of nano- and micron-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS: In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS: Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION: Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.
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Atherosclerosis (AS) is a chronic inflammatory disorder characterized by arterial intimal lipid plaques. Small interfering ribonucleic acid (siRNA)-based therapies, with their ability to suppress specific genes with high targeting precision and minimal side effects, have shown great potential for AS treatment. However, targets of siRNA therapies based on macrophages for AS treatment are still limited. Olfactory receptor 2 (Olfr2), a potential target for plaque formation, was discovered recently. Herein, anti-Olfr2 siRNA (si-Olfr2) targeting macrophages was designed, and the theranostic platform encapsulating si-Olfr2 to target macrophages within atherosclerotic lesions was also developed, with the aim of downregulating Olfr2, as well as diagnosing AS through photoacoustic imaging (PAI) in the second near-infrared (NIR-II) window with high resolution. By utilization of a reactive oxygen species (ROS)-responsive nanocarrier system, the expression of Olfr2 on macrophages within atherosclerotic plaques was effectively downregulated, leading to the inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and interleukin-1 ß (IL-1ß) secretion, thereby reducing the formation of atherosclerotic plaques. As manifested by decreased Olfr2 expression, the lesions exhibited a significantly alleviated inflammatory response that led to reduced lipid deposition, macrophage apoptosis, and a noticeable decrease in the necrotic areas. This study provides a proof of concept for evaluating the theranostic nanoplatform to specifically deliver si-Olfr2 to lesional macrophages for AS diagnosis and treatment.
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Multidrug resistance (MDR) of tumors is one of the main reasons for the failure of chemotherapy. Multidrug resistance refers to the cross-resistance of tumor cells to multiple antitumor drugs with different structures and mechanisms of action. Current strategies to reverse multidrug resistance in tumors include MDR inhibitors and RNAi technology. siRNA is a small molecule RNA that is widely used in RNAi technology and has the characteristics of being prepared in large quantities and chemically modified. However, siRNA is susceptible to degradation in vivo. The effect of siRNA therapy alone is not ideal, so siRNA and anticancer drugs are administered in combination to reverse the MDR of tumors. Non-viral vectors are now commonly used to deliver siRNA and anticancer drugs to tumor sites. This article will review the progress of siRNA and chemotherapeutic drug delivery systems and their mechanisms for reversing multidrug resistance.
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Anxiety and depression are central nervous system illnesses that are among the most prevalent medical concerns of the twenty-first century. Patients with this condition and their families bear psychological, financial, and societal hardship. There are currently restrictions when utilizing the conventional course of treatment. RNA interference is expected to become an essential approach in anxiety and depression due to its potent and targeted gene silencing. Silencing of genes by post-transcriptional modification is the mechanism of action of small interfering RNA (siRNA). The suppression of genes linked to disease is typically accomplished by siRNA molecules in an efficient and targeted manner. Unfavourable immune responses, off-target effects, naked siRNA instability, nuclease vulnerability, and the requirement to create an appropriate delivery method are some of the challenges facing the clinical application of siRNA. This review focuses on the use of siRNA in the treatment of anxiety and depression.
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Breast cancer (BC) is the most common and malignant tumor diagnosed in women, with 2.9 million cases in 2023 and the fifth highest cancer-causing mortality worldwide. Recent developments in targeted therapy options for BC have demonstrated the promising potential of small interfering RNA (siRNA)-based cancer therapeutic approaches. As BC continues to be a global burden, siRNA therapy emerges as a potential treatment strategy to regulate disease-related genes in other types of cancers, including BC. siRNAs are tiny RNA molecules that, by preventing their expression, can specifically silence genes linked to the development of cancer. In order to increase the stability and effectiveness of siRNA delivery to BC cells, minimize off-target effects, and improve treatment efficacy, advanced delivery technologies such as lipid nanoparticles and nanocarriers have been created. Additionally, combination therapies, such as siRNAs that target multiple pathways are used in conjunction with conventional chemotherapy agents, have shown synergistic effects in various preclinical studies, opening up new treatment options for breast cancer that are personalized and precision medicine-oriented. Targeting important genes linked to BC growth, metastasis, and chemo-resistance has been reported in BC research using siRNA-based therapies. This study reviews recent reports on therapeutic approaches to siRNA for advanced treatment of BC. Furthermore, this review evaluates the role and mechanisms of siRNA in BC and demonstrates the potential of exploiting siRNA as a novel target for BC therapy.