Current gene therapy最新文献

Background: The increasing frequency of global pandemics, such as COVID-19, H1N1, and Ebola, highlights the urgent need for innovative vaccine technologies that enable rapid response and broader accessibility. Nanovaccines, leveraging nanotechnology for targeted antigen delivery and enhanced immune activation, have emerged as a promising solution for improving vaccine efficacy, stability, and distribution.

Objective: This review examines the role of nano vaccines in pandemic preparedness, focusing on their benefits, mechanisms of action, recent advancements, and the challenges associated with their development and deployment.

Methods: A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Web of Science. Research articles and clinical trial data from the past decade were analyzed, with a focus on nano-vaccine platforms, immune response mechanisms, and global deployment strategies.

Key findings: Nanovaccines offer accelerated development timelines, enhanced antigen presentation, and prolonged immune responses via platforms including lipid-based nanoparticles, polymeric systems, virus-like particles, and inorganic nanoparticles. The success of mRNA vaccines during COVID-19 has demonstrated the transformative potential of nanotechnology in vaccine development. However, significant challenges remain, including safety concerns, large-scale manufacturing, regulatory approval procedures, and equitable access, particularly in low- and middle-income countries.

Conclusion: Nanovaccines offer substantial promise for global pandemic preparedness. Tackling current challenges through international collaboration, policy support, and increased investment will be essential for ensuring their widespread adoption. Developing nanotechnology-driven vaccine solutions can strengthen global health resilience and enable faster, more effective responses to future pandemics.

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a transformative approach in oncology, particularly for hematologic malignancies. However, its application to solid tumors, such as ovarian cancer, remains challenging. This review discusses recent advancements in CAR-T cell therapy specifically targeting ovarian cancer, with a focus on current strategies and future directions. We first introduce the fundamental structure of CARs, detailing the core components including the antigen-binding domain, the transmembrane domain, and the signaling domains. The optimization of CAR-T design is then examined, highlighting innovative strategies such as bispecific CAR-Ts, co-expression CAR-Ts, fine-tuning of CAR constructs, and cytokine-modified CAR-Ts. The review further explores a comprehensive array of antigen targets relevant to ovarian cancer, ranging from HER2 and mesothelin to more novel targets like CD47 and L1CAM. Additionally, we investigate how nanotechnology is enhancing CAR-T cell therapy for solid tumors, with specific attention to mRNA delivery systems, liposomal nanoparticles, hydrogel-based platforms, and the integration of photothermal therapy.

Glioblastoma remains one of the most lethal brain tumors with limited therapeutic options and a dismal survival rate, largely due to its highly complex Tumor Microenvironment (TME) and frequent drug resistance. In response, three-dimensional (3D) organoid technology has emerged as a powerful tool for modeling glioblastoma, offering a physiologically relevant in vitro system that closely mimics the in vivo architecture, cellular heterogeneity, and drug response of human tumors. Unlike traditional 2D cultures or animal models, glioblastoma organoids enable highthroughput drug screening, personalized therapy testing, and early diagnostic research by preserving key features of the TME. However, despite their immense promise, current organoid models face substantial limitations, including the absence of immune components, functional vasculature, and region-specific neuronal subtypes, thereby restricting their full translational potential, especially for immunotherapy studies. Existing models, such as genetically engineered cerebral organoids (Neo- Cor) and glioblastoma spheroid co-cultures (GLICO), either fail to reflect patient heterogeneity or are constrained by time-intensive preparation. Additionally, patient-derived organoids may lose genetic fidelity over prolonged culture. The novelty of this work lies in its advocacy for engineered cell-based strategies and Adult Stem Cell (AdSC)-derived organoids to overcome these challenges. By enhancing the intrinsic properties of organoid cells and integrating endothelial and immune components, this approach offers a next-generation platform for more accurate modeling of glioblastoma, with greater relevance for drug responsiveness, chemosensitization studies, gene editing, and regenerative applications. This distinguishes the present work from previous studies by not only identifying the gaps in current organoid technologies but also proposing specific, actionable improvements that bring organoid culture closer to clinical translation in glioblastoma research.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non- Hodgkin lymphoma. Despite its high prevalence, treatment options remain limited, and molecular mechanisms underlying its pathogenesis remain poorly understood. This study aimed to identify potential biomarkers for DLBCL by integrating microarray analysis, Mendelian randomization (MR), and experimental validation.

Materials and methods: DLBCL-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify hub genes in DLBCL. Moreover, we integrated genome-wide association studies data with expression quantitative trait loci to identify genes with potential causal relationships to DLBCL. The predictive power of the identified biomarker gene was evaluated using receiver operating characteristic (ROC) curves. Functional experiments were conducted to elucidate the biological roles of this gene.

Results: Differential expression analysis and WGCNA identified 119 differentially expressed genes and 156 central genes, resulting in the identification of 16 hub genes in DLBCL. MR analysis revealed 188 genes with significant causal associations with DLBCL, ultimately identifying nucleolar protein 10 (NOP10) as a key biomarker. NOP10 demonstrated strong predictive performance, with the area under the curve values consistently above 0.852 across all datasets. Experimental validation in DLBCL cell lines showed that NOP10 knockdown significantly inhibited cell proliferation, induced apoptosis, and reduced the migratory capacity.

Discussion: Although recent studies have made progress in identifying biomarkers associated with lymphoma onset and progression, establishing causality remains challenging due to reverse causation and confounding factors. The integration of MR in this study addressed these limitations by inferring the causality between exposure and outcome. Our findings were experimentally validated. The combination of microarray analysis and MR in our analytical approach provides a robust framework for identifying biomarker genes in various diseases and guiding the development of future therapeutic strategies.

Conclusion: Our study has identified NOP10 as a promising biomarker of DLBCL, providing potential insights into the molecular mechanisms underlying this disease. Moreover, a multi-method approach integrating microarray analysis, MR, and experimental validation has established a robust framework for advancing biomarker discovery and identifying therapeutic targets for various diseases.

Background: Small RNAs play a pivotal role in gene regulation, mediating RNAinduced transcriptional activation and post-transcriptional gene silencing. Their high specificity and versatility make them indispensable tools for investigating gene function, elucidating disease mechanisms, and developing targeted therapeutic strategies.

Methods: We developed an AuNP-based RNA delivery system to enhance stability and uptake of therapeutic RNAs targeting TP53 and KRAS pathways. AuNPs were synthesized via citrate reduction and conjugated with siRNA.923 (KRAS-targeting siRNA) and dsP53-285 (p53-stimulating saRNA). A549 and HCT116 cells were transfected with conjugates. Gene expression was analyzed by RT-qPCR and Western blotting. Functional assays, including flow cytometry for cell cycle and apoptosis, MTT and colony formation assays for proliferation, and transwell assays for migration and invasion, were conducted.

Results: Individual transfection of AuNP-conjugated siRNA.923 effectively downregulated KRAS expression, whereas AuNP-dsP53-285 upregulated TP53 expression in both A549 and HCT116 cell lines. Co-transfection with AuNP-siRNA.923/dsP53-285 resulted in a significantly greater increase in TP53 mRNA and protein levels, without affecting KRAS mRNA or protein levels, in both cell lines compared with individual transfections. Functionally, the AuNP-based dual small RNA delivery system induced cell cycle arrest at the G0/G1 phase, significantly enhanced apoptosis, and markedly reduced cell proliferation, colony formation, migration, and invasion relative to individual RNA transfections.

Conclusion: These findings demonstrate that AuNP-mediated co-delivery of siRNA and saRNA effectively modulates the KRAS-p53 signaling axis and enhances therapeutic potential in KRASmutant, TP53-wild-type cancers. Further studies, including in vivo investigations, are warranted to evaluate the translational feasibility and clinical relevance of this combinatorial approach.

The development of traditional antibiotics has stalled due to an escalating antimicrobial resistance (AMR) crisis. Generating new antibiotic development paradigms is critically important. CRISPR-Cas9 gene-editing technology, originally derived from the bacteria's immune system, is now being repurposed to target and neutralize antimicrobial resistance, effectively turning the bacteria's defence mechanisms against them. In this editorial, we outline the opportunities for CRISPRCas9 technology to break the microbial resistance paradigm through specific gene disruption, plasmid targeting, phage therapy, and population-based interventions. We summarize some advances related to CRISPR-Cas9 technology, including a brief overview of the technology, its component technologies, potential applications of genetic targeting, recent research related to the technology, near-future developments, and challenges. As we face an era that has been termed the "postantibiotics" era, CRISPR-Cas9 technology not only represents exciting technology, but also a necessary transitional change for antimicrobial products. This editorial explores recent innovations and data highlighting CRISPR-Cas9's role in addressing AMR, and the scientific, regulatory, and ethical pathways to realizing its full potential in clinical settings.

Anticancer drug therapy primarily focuses on exploiting genetic alterations that already exist in tumour cells. This understanding can help to utilize the conventional therapeutics with much better results. The identification of genes whose loss of function alters the tumor growth, enhances the cytotoxic characterises or leads to enhancement in the apoptotic nature of tumor cells can be done by the use of Loss-of-function genetic screens. In this review, we summarise RNAbased therapies, including mechanisms of action, clinical applications, and advancements with nanoparticles and artificial intelligence for tumor targeting in cancer. Many techniques are being explored for the promotion of RNA tracking of intracellular activities and production of metabolic stability. The emerging role of RNA in diagnosis and treatment has been a topic of discussion in the field of medical sciences. Different types of RNAs, such as small interfering RNA (siRNA), microRNA (miRNA), etc and Exosomes RNA delivery are being used for employment as the delivery system, which are considered as the therapeutic targeting system. 56 mRNA drugs have been in the pipeline for entering the clinical pipeline and nearly 108 oligonucleotide drugs are entering the clinical pipeline worldwide, including ASOs, siRNAs, aptamers and miRNAs. These different types, although they assist each other in their proper working and still function in very different ways. Most of these are under investigation, while some have been approved for clinical use. RNA-based therapies hold great potential for cancer treatment due to their specificity and adaptability. Continued research into improving delivery methods, reducing side effects, and exploring new RNA targets will be crucial in advancing these therapies to clinical practice.

Introduction: Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) is a highly prevalent female malignancy. As the epigenomic characteristics of immune cells and cancer cells can serve as predictive indicators for the response to cancer immunotherapy, analysis of epigenetically modified genes (EpiGenes) could contribute to CESC treatment.

Methods: The ssGSEA algorithm was employed to compute EpiGenes scores. Core genes that exhibited significant module association and a close correlation with EpiGenes scores were identified via the WGCNA package. Univariate Cox proportional hazards regression was performed on the core genes using the survival package, followed by gene set reduction via LASSO Cox regression. Ultimately, key genes were determined through multivariate Cox regression to establish a RiskScore model. Further, the optimal risk cutoff was determined using the survminer package to stratify CESC patients into high- and low-risk subgroups. For enrichment analysis, clusterProfiler and GSEA were utilized. Immune infiltration across risk groups was evaluated via ssGSEA, the MCPcounter algorithm, and the ESTIMATE algorithm. TIDE was employed to compare immunotherapeutic responses between the risk groups, while the pRRophetic software was utilized to predict patients' chemotherapeutic drug sensitivity. The biomarkers identified were validated by performing in vitro experiments.

Results: CEP78, DOCK7, DPY19L4, and POM121 were identified by computational analyses as the key genes for CESC and further validated through in vitro experiments. Pathway enrichment analysis revealed predominant enrichment in immune-related pathways in the high-risk group, whereas the low-risk group was more enriched in energy and metabolic pathways. A significant negative correlation was observed between CD8+ T cell abundance and RiskScore, with higher ESTIMATEScores and StromalScores in high-risk patients. Notably, the high-risk group also demonstrated lower potential sensitivity to immunotherapy but more active responsiveness to a broader spectrum of chemotherapeutic agents.

Discussion: Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that module genes are significantly enriched in cell cycle regulatory pathways, and these genes, in conjunction with Human Papillomavirus (HPV) infection-induced cell cycle dysregulation, jointly participate in CESC pathogenesis, providing a mechanistic basis for understanding the disease.

Conclusion: This study provided novel theoretical evidence for immunotherapy and chemotherapy selection in the management of CESC.

Background: Human metapneumovirus (HMPV) is a respiratory virus that presents symptoms similar to those of the common cold or influenza, including cough, nasal congestion, sore throat, fever, wheezing, and shortness of breath. The primary mode of transmission is through respiratory droplets from an infected person's cough or sneeze, as well as through contact with contaminated surfaces. HMPV was first recognized in 2001 and poses a significant public health concern, particularly affecting vulnerable groups like children, the elderly, and those with weakened immune systems. Its impact is notably severe in children under five years, contributing to rates of infant mortality. The main goal of the review article is to improve public health by gathering vital information on the human metapneumovirus (HMPV) and how it affects respiratory illnesses. It seeks to advance knowledge of these illnesses and methods of response.

Methods: A thorough literature search was performed utilizing databases concentrating on studies published up to May 2025. The selection criteria were based on comprehensive prior research concerning human metapneumovirus on a global scale.

Result: HMPV (Human Metapneumovirus) undergoes gradual mutations, leading to the emergence of new strains that are derived from previously circulating variants. Clinical features associated with different HMPV genotypes exhibit moderate variations, indicating some diversity in how the virus presents in patients. Notably, no significant seasonal trends have been observed in the incidence of HMPV infections, suggesting that the virus does not follow typical seasonal patterns seen with other respiratory viruses. In terms of severity, HMPV infections are generally less severe compared to those caused by Human Respiratory Syncytial Virus (HRSV). However, co-infection with both HMPV and RSV in young children has been linked to more severe illness than infections with either virus alone, highlighting the potential for compounded health risks in this demographic. Additionally, children hospitalized with HMPV are at an increased risk of developing acute kidney injury (AKI), with this risk correlating with age, independent of the severity of respiratory symptoms or existing comorbidities. Despite a significant increase in testing for respiratory viruses during the COVID-19 pandemic, the overall incidence of HMPV has remained stable, indicating that the pandemic did not lead to a surge in HMPV cases.

Discussion: The evolutionary path of HMPV, marked by gradual mutations derived from earlier strains, restricts its ability to cause widespread pandemics. This view is supported by the lack of notable seasonal fluctuations and generally milder clinical impact compared to HRSV. Nonetheless, the rise in severity observed during co-infections highlights the need for accurate diagnosis and thorough monitoring. Many individuals' pre

Introduction: Epithelial Ovarian Cancer (EOC) is a highly aggressive gynecological malignancy with a high mortality rate primarily due to late-stage diagnosis and metastatic dissemination. Regulatory T cells (Tregs) have emerged as critical mediators of immune evasion, yet the role of Foxp3⁺ Tregs in modulating Tumor-Associated Macrophage (TAM) polarization and the underlying molecular mechanisms in EOC remains unclear.

Methods: An orthotopic EOC mouse model and in vitro co-culture systems were employed to investigate the effects of Foxp3⁺ Tregs on TAM polarization. Quantitative Real-Time PCR (qRTPCR), flow cytometry, Western blotting, wound healing, and transwell assays were performed to assess gene expression, immune cell infiltration, and tumor cell migration/invasion. Foxp3 knockdown was achieved using Adeno-Associated Virus (AAV)-mediated delivery to evaluate its effects in vivo.

Results: Foxp3⁺ Tregs induced macrophage polarization toward the M2 phenotype, characterized by downregulation of M1 markers (IL-1β, iNOS) and upregulation of M2 markers (IL-10, Arg-1). Mechanistically, Foxp3⁺ Tregs activated the Sirt1-ERK1/2-STAT3 signaling pathway while suppressing NF-κB activity. In vitro, Foxp3⁺ Tregs enhanced the migratory and invasive capacities of ovarian cancer cells, whereas in vivo Foxp3 knockdown significantly reduced tumor growth and M2 macrophage infiltration.

Discussion: These findings suggest that Foxp3⁺ Tregs play a pivotal role in shaping the immunosuppressive tumor microenvironment in EOC by promoting M2 macrophage polarization through Sirt1-ERK1/2-STAT3 signaling and NF-κB suppression, ultimately facilitating tumor progression.

Conclusion: Foxp3⁺ Tregs drive immunosuppressive macrophage polarization and ovarian cancer progression, highlighting Foxp3 as a potential therapeutic target for EOC treatment.