Molecular Therapy. Nucleic Acids最新文献_第5页

RNAi delivery mediated by milk extracellular vesicles in colon cancer. 乳细胞外囊泡介导的结肠癌RNAi传递。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-31 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102644

Jessie Santoro, Silvia Nuzzo, Andrea Soricelli, Marco Salvatore, Anna Maria Grimaldi

{"title":"RNAi delivery mediated by milk extracellular vesicles in colon cancer.","authors":"Jessie Santoro, Silvia Nuzzo, Andrea Soricelli, Marco Salvatore, Anna Maria Grimaldi","doi":"10.1016/j.omtn.2025.102644","DOIUrl":"10.1016/j.omtn.2025.102644","url":null,"abstract":"Small interfering RNA (siRNA) has emerged as a powerful tool for gene silencing, offering great potential for therapeutic applications. However, the clinical use of siRNA is limited by several challenges, including poor stability in biological fluids, off-target effects, and toxicity due to non-specific cellular uptake. To address these limitations, extracellular vesicles (EVs) derived from milk are being investigated as natural carriers to deliver siRNA and microRNA. These EVs offer advantages such as low immunogenicity, biocompatibility, and the ability to cross biological barriers. Here, we optimized methods for loading siRNA into milk-derived EVs (mEVS) and assessed their ability to protect siRNA from degradation while preserving its gene-silencing efficacy. We targeted a potential biomarker, Aurora kinase A (AURKA), known to be deregulated in many types of solid tumors, including colon cancer. Our results demonstrate that mEVs-loaded siRNA retains the stability and functionality of internalized siRNA, leading to efficient gene silencing in target cells. This approach highlights the potential of mEVs as a safe and valuable delivery system, overcoming key limitations of siRNA therapeutics and opening new avenues and opening new avenues for diagnostic and therapeutic strategies in colon cancer.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102644"},"PeriodicalIF":6.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

mRNA-LNP vaccine encoding the Plasmodium vivax circumsporozoite protein is highly immunogenic and confers protection in mice. 编码间日疟原虫环孢子子蛋白的mRNA-LNP疫苗具有高度免疫原性，在小鼠中具有保护作用。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-30 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102645

Amporn Limsalakpetch, Utaiwan Kum-Arb, Kosol Yongvanitchit, Rawiwan Im-Erbsin, Ratawan Ubalee, Norman Waters, Brian A Vesely, Hiromi Muramatsu, Drew Weissman, Ying K Tam, Shigeto Yoshida, John Adams, Anjali Yadava, Norbert Pardi, Sathit Pichyangkul

{"title":"mRNA-LNP vaccine encoding the Plasmodium vivax circumsporozoite protein is highly immunogenic and confers protection in mice.","authors":"Amporn Limsalakpetch, Utaiwan Kum-Arb, Kosol Yongvanitchit, Rawiwan Im-Erbsin, Ratawan Ubalee, Norman Waters, Brian A Vesely, Hiromi Muramatsu, Drew Weissman, Ying K Tam, Shigeto Yoshida, John Adams, Anjali Yadava, Norbert Pardi, Sathit Pichyangkul","doi":"10.1016/j.omtn.2025.102645","DOIUrl":"10.1016/j.omtn.2025.102645","url":null,"abstract":"Plasmodium vivax poses significant challenges to malaria control due to its relapsing nature. This study explores the immunogenicity and efficacy of nucleoside-modified mRNA-lipid nanoparticle (LNP) vaccines targeting the P. vivax circumsporozoite protein (PvCSP). Two mRNA constructs encoding PvCSP were designed and tested in mice. Despite lower protein expression, the vaccine encoding the wild-type signal peptide (SP) and glycosylphosphatidylinositol (GPI) anchor of PvCSP induced significantly higher antibody titers against the PvCSP and its repeat region compared with the mRNA construct with SP but without GPI. The immunogenicity of PvCSP mRNA-LNP vaccines was evaluated using various administration routes and immunization schedules. Both intradermal and intramuscular delivery generated dose-dependent antibody responses, but the former demonstrated superior responses at a lower dose. Conversely, intravenous administration resulted in very poor responses. Notably, administering a delayed third dose intramuscularly 5 months after the second dose resulted in significantly higher levels of anti-repeat region antibodies and enhanced T cell responses in both the spleen and liver. This delayed regimen provided strong protection against sporozoite challenge, with the magnitude and avidity of anti-repeat region antibodies linked to this protection. These findings highlight the potential of the nucleoside-modified mRNA-LNP vaccine platform in combating P. vivax pre-erythrocytic stage infection.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102645"},"PeriodicalIF":6.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies. 铁下垂作为胶质母细胞瘤的治疗靶点：机制和新兴策略。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-30 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102649

Samine Mashayekhi, Hossein Majedi, Ahmad Reza Dehpour, Samaneh Dehghan, Maryam Jafarian, Mahmoudreza Hadjighassem, Saereh Hosseindoost

{"title":"Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies.","authors":"Samine Mashayekhi, Hossein Majedi, Ahmad Reza Dehpour, Samaneh Dehghan, Maryam Jafarian, Mahmoudreza Hadjighassem, Saereh Hosseindoost","doi":"10.1016/j.omtn.2025.102649","DOIUrl":"10.1016/j.omtn.2025.102649","url":null,"abstract":"Glioblastoma multiforme (GBM) is the most prevalent malignant brain tumor. Treating this type of cancer is challenging due to its high heterogeneity, rapid cell growth, and highly malignant nature, which results in a poor prognosis. A key feature of GBM's malignancy is that it resists drug treatments and evades cell death mechanisms. Ferroptosis is a promising therapeutic avenue for combating drug-resistant cancers because it is a recently discovered mechanism of programmed cell death that oxidizes membrane lipids and is triggered by an accumulation of reactive oxygen species. Recent findings suggest that ferroptosis is an innovative path for improving human GBM therapy. More exploration of the regulatory pathways and interactions of ferroptosis is essential to developing effective therapeutic strategies for this aggressive type of cancer. Inducing ferroptosis or integrating it with current treatments may present an opportunity to improve outcomes in GBM patients. This review investigates the role of ferroptosis in GBM and identifies its important molecular mediators. It also explores promising therapeutic strategies that target ferroptosis as a novel approach for GBM treatment.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102649"},"PeriodicalIF":6.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

circARHGAP10 as a candidate biomarker and therapeutic target in myotonic dystrophy type 1. circARHGAP10作为1型肌强直性营养不良的候选生物标志物和治疗靶点。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-30 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102646

Denisa Baci, Spyros Tastsoglou, Claudia Provenzano, Alessandra Perfetti, Mariapaola Izzo, Mario Lisanti, Svetlana Frolova, Christine Voellenkle, Anna Sofia Tascini, Rosanna Cardani, Beatrice Cardinali, Giovanni Meola, Germana Falcone, Fabio Martelli

{"title":"circARHGAP10 as a candidate biomarker and therapeutic target in myotonic dystrophy type 1.","authors":"Denisa Baci, Spyros Tastsoglou, Claudia Provenzano, Alessandra Perfetti, Mariapaola Izzo, Mario Lisanti, Svetlana Frolova, Christine Voellenkle, Anna Sofia Tascini, Rosanna Cardani, Beatrice Cardinali, Giovanni Meola, Germana Falcone, Fabio Martelli","doi":"10.1016/j.omtn.2025.102646","DOIUrl":"10.1016/j.omtn.2025.102646","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the 3'-UTR of the DMPK gene that lead to nuclear foci accumulation and splicing defects. Circular RNAs (circRNAs) are emerging regulators of muscular disorders, but their role in DM1 remains largely unknown. By analyzing available RNA-sequencing datasets from DM1 patients, followed by validation in patients and matching control muscle biopsies, we identified seven circRNAs that were significantly increased in DM1 muscles and displayed high circular-to-linear isoform ratios. Among them, circARHGAP10 correlated positively with CTG repeat length and inversely with muscle strength, indicating its potential as a biomarker. Silencing of circARHGAP10 in DM1 myogenic cells reduced DMPK expression, decreased nuclear foci, and partially rescued normal splicing. Bioinformatics prediction and pull-down of circARHGAP10 indicated that circARHGAP10 binds miR-409-3p. circARHGAP10 and miR-409-3p were both found to be upregulated in DM1 muscle biopsies and silencing of circARHGAP10 led to the downregulation of miR-409-3p, indicating their co-regulation. Interestingly, miR-409-3p overexpression blocked the beneficial effects of circARHGAP10 silencing on DMPK levels, foci, and splicing. Thus, circARHGAP10-dependent regulation of DM1-associated mechanisms is mediated, at least in part, via interaction with miR-409-3p. In conclusion, circARHGAP10 exhibits promising potential as a biomarker and therapeutic target for DM1.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102646"},"PeriodicalIF":6.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of synthetic mRNA with selected UTR sequences and alternative poly(A) tail, in vitro and in vivo. 体外和体内对选定UTR序列和备选多聚(A)尾部合成mRNA的评价。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-30 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102648

Ayoub Medjmedj, Hugo Genon, Dounia Hezili, Albert Ngalle Loth, Rudy Clemençon, Cyril Guimpied, Lucile Mollet, Anne Bigot, Frank Wien, Josef Hamacek, Clément Chapat, Federico Perche

{"title":"Evaluation of synthetic mRNA with selected UTR sequences and alternative poly(A) tail, in vitro and in vivo.","authors":"Ayoub Medjmedj, Hugo Genon, Dounia Hezili, Albert Ngalle Loth, Rudy Clemençon, Cyril Guimpied, Lucile Mollet, Anne Bigot, Frank Wien, Josef Hamacek, Clément Chapat, Federico Perche","doi":"10.1016/j.omtn.2025.102648","DOIUrl":"10.1016/j.omtn.2025.102648","url":null,"abstract":"Messenger RNA (mRNA) has emerged as an attractive new technology of drugs. The efficacy of mRNA technology depends on both the efficiency of mRNA delivery and translation. Untranslated regions (UTRs) and the poly(A) tail play a crucial role in regulating mRNA intracellular kinetics. Intending to improve the therapeutic potential of synthetic mRNA, we evaluated various UTRs and tail designs, using Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine sequences as a reference. First, we screened six 5' UTRs (cap-dependent/-independent), evaluated nine 5' UTR-3' UTR combinations, and a novel heterologous A/G tail in cell models, and in vivo using luciferase as a reporter gene. Then, to decipher the translation mechanism of selected UTRs, we correlated mRNA expression with ribosome load, mRNA half-life, mRNA immunogenicity, and UTR structures. Our results showed that the heterologous tail we introduced is as potent as the Pfizer-BioNTech tail and confirmed the high potency of the human α-globin 5' UTR. They also revealed the potential of the VP6 and SOD 3' UTRs. We validated our results using mRNA encoding the SARS-CoV-2 spike protein formulated as lipid nanoparticles (LNPs) for mouse immunization. Overall, the selected 3' UTRs and heterologous A/G tail have great potential as new elements for therapeutic mRNA design.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102648"},"PeriodicalIF":6.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A short peptide for efficient cellular mRNA delivery: A potential application for inducing an immune response. 用于有效细胞mRNA传递的短肽：诱导免疫应答的潜在应用。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-29 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102650

Clémentine Ayélé Teko-Agbo, Emilie Josse, Karidia Konate, Sébastien Deshayes, Pascal de Santa Barbara, Sandrine Faure, Prisca Boisguérin, Eric Vivès

{"title":"A short peptide for efficient cellular mRNA delivery: A potential application for inducing an immune response.","authors":"Clémentine Ayélé Teko-Agbo, Emilie Josse, Karidia Konate, Sébastien Deshayes, Pascal de Santa Barbara, Sandrine Faure, Prisca Boisguérin, Eric Vivès","doi":"10.1016/j.omtn.2025.102650","DOIUrl":"10.1016/j.omtn.2025.102650","url":null,"abstract":"Nucleic acid molecules are emerging as potential therapeutic tools, as evidenced by the transfection of small interfering RNA (siRNA) molecules in therapeutic applications and messenger RNAs in immunotherapeutic vaccination. In most cases, these nucleic acids are conditioned as lipid nanoparticles made with different lipid moieties to promote their intracellular delivery. Over the past few years, we have documented the delivery of siRNAs using a single short (15 amino acids) peptide called WRAP5, which follows an extremely simplified formulation phase that enables the formation of nanoparticles with a diameter of 60-80 nm. We indeed demonstrated the expected dose-response reduction in the levels of the targeted proteins. To apply this technology to the cellular delivery of mRNAs, we investigated the ability of the WRAP5 peptide to transfect mRNAs of different sizes and promote the expression of their proteins. These peptide-based nanoparticles, which also have diameters ranging from 60 to 80 nm, showed remarkable stability over time when simply stored at 4°C and fully retained their transfection properties in vitro for up to several months post-formulation. Interestingly, we demonstrated in vivo that these nanoparticles were able to induce an immune response against the protein synthesized from the vectorized mRNA.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102650"},"PeriodicalIF":6.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic insights into circularization via Anabaena group I intron-based scarless circular RNA. 通过Anabaena I组内含子基无疤痕环状RNA对环状化的机制见解。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-17 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102626

Bangda Fan, Sujia Liu, Yinghuan Xu, Xinghuan Ma, Wenbin Qi, Lei Miao, Lin Liu, Shubo Du, Jiaqi Lin

{"title":"Mechanistic insights into circularization via Anabaena group I intron-based scarless circular RNA.","authors":"Bangda Fan, Sujia Liu, Yinghuan Xu, Xinghuan Ma, Wenbin Qi, Lei Miao, Lin Liu, Shubo Du, Jiaqi Lin","doi":"10.1016/j.omtn.2025.102626","DOIUrl":"10.1016/j.omtn.2025.102626","url":null,"abstract":"Circular RNA (circRNA) offers significant advantages in stability, storage, manufacturing, and pharmacokinetics, making it an attractive option for therapeutic applications over linear RNA. However, the commonly used permuted intron-exon (PIE) method for constructing circRNA introduces an exogenous \"scar\" sequence during splicing initiation, potentially compromising circRNA potency and inducing immunogenicity. Through exploration of the molecular mechanism of the Anabaena group I intron splicing, we conclude the sequence characterization of splice sites and the recognition rules of IG sequence. Leveraging these principles, we successfully prepared \"scarless\" circRNA without sacrificing its circularization efficiency using standard in vitro transcription procedures. Immunogenicity analysis of scarless circRNAs revealed that the scar will not induce an immune response, consistent with previous findings, after complete removal of linear byproducts, that circRNAs are naturally low immunogenicity. Finally, we find that the incorporation of modified nucleotides in circRNAs disrupts not only splicing function but also internal ribosome entry site function, with a low percentage of modified nucleotides destroying translation capacity.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102626"},"PeriodicalIF":6.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thermostable unit solid dose formulations for subcutaneous administration of DNA vaccines. 用于DNA疫苗皮下注射的耐热单位固体剂量制剂。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-07-17 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102628

Pablo Garcia-Valtanen, Arthur E L Yeow, Zelalem A Mekonnen, Dawn M Whelan, Ryan Santos, Zahraa Al-Delfi, Susana Rodrigues, Pauline Gavan, Keith Howard, Makutiro G Masavuli, Branka Grubor-Bauk

{"title":"Thermostable unit solid dose formulations for subcutaneous administration of DNA vaccines.","authors":"Pablo Garcia-Valtanen, Arthur E L Yeow, Zelalem A Mekonnen, Dawn M Whelan, Ryan Santos, Zahraa Al-Delfi, Susana Rodrigues, Pauline Gavan, Keith Howard, Makutiro G Masavuli, Branka Grubor-Bauk","doi":"10.1016/j.omtn.2025.102628","DOIUrl":"10.1016/j.omtn.2025.102628","url":null,"abstract":"The coronavirus disease 2019 pandemic has highlighted the critical need for thermostable vaccines to ensure equitable distribution and accessibility, particularly in regions lacking cold chain infrastructure. Here we present a thermostable, solid dose DNA vaccine (SDV) platform for subcutaneous delivery, based on a sugar-sugar alcohol-polymer formulation manufactured via lyophilization and compaction. Using luciferase-expressing plasmid as a model, we demonstrate that subcutaneous vaccination with SDV formulation of C57BL/6 mice results in efficient and durable transgene expression in vivo. In vitro stability assays confirmed that the SDV formulation maintained excellent thermostability after 30 days of storage at 4°C, 25°C, 37°C, and 42°C. We next applied the SDV platform to a Zika virus (ZIKV) NS1 DNA vaccine and immunized BALB/c mice. ZIKV-SDV vaccination elicited robust NS1-specific antibody and T cell responses, and conferred protection upon ZIKV challenge. These data establish the feasibility of lyophilized SDV DNA vaccines for needle-free thermostable delivery. By eliminating the need for reconstitution, refrigeration, and skilled administration, SDV formulation has the potential to enhance the deployment, cost effectiveness, and shelf-life of DNA vaccines in resource-limited settings.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102628"},"PeriodicalIF":6.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Manipulating the delivery and immunogenicity of DNA vaccines through the addition of CB[8] to cationic polymers. 通过向阳离子聚合物中添加CB[8]来操纵DNA疫苗的递送和免疫原性。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-06-30 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102585

Hadijatou J Sallah, Benjamin T Cheesman, David J Peeler, Andrew M Howe, Robin J Shattock, Roger Coulston, John S Tregoning

{"title":"Manipulating the delivery and immunogenicity of DNA vaccines through the addition of CB[8] to cationic polymers.","authors":"Hadijatou J Sallah, Benjamin T Cheesman, David J Peeler, Andrew M Howe, Robin J Shattock, Roger Coulston, John S Tregoning","doi":"10.1016/j.omtn.2025.102585","DOIUrl":"10.1016/j.omtn.2025.102585","url":null,"abstract":"Challenges with vaccine reactogenicity, stability, and access have highlighted the need to develop alternative strategies for formulation and delivery. We explored the incorporation of cucurbit[n]urils (CBs), as supramolecular \"hosts,\" into nucleic acid-polymer polyplexes. CBs are small, non-toxic, barrel-shaped molecules that transiently crosslink polymers containing supramolecular \"guests,\" thereby increasing molecular weight (MW) of the complex, a correlate of transfection efficiency. We tested whether the supramolecular interactions of CB[8] impact polyplex function. We generated a library of different CB[8] polyplexes using plasmid DNA (pDNA), varying N/P (the ratio of polymer to plasmid), the length, and guest (phenylalanine [Phe]) group frequency of the polyethylenimine (PEI) polymer backbone. We found that N/P 32 and the 20Phe1 (20kDa PEI with 1 mol% Phe) gave optimal gene expression and that incorporating CB[8] in polyplex formulations improved gene expression, both in vitro and in vivo. Despite increases in gene expression, inclusion of CB[8] in formulations with higher guest-binding capacity led to decreased immunogenicity, possibly as a result of dampened innate immune responses. Our data show that CB[8] polyplexes increase gene delivery and expression but alter inflammatory responses. These findings highlight that rational design of the CB[8] polymer system can enable nucleic acid delivery for both vaccine and therapeutic applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102585"},"PeriodicalIF":6.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12447565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA activation of CEBPA improves leukemia treatment. RNA激活CEBPA可改善白血病治疗。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-06-16 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102611

Olivia Kovecses, Bahram Sharif-Askari, Cristobal Gonzalez-Losada, Vikash Reebye, Bríd M Ryan, Nathan W Luedtke, François E Mercier, Maureen McKeague

{"title":"RNA activation of CEBPA improves leukemia treatment.","authors":"Olivia Kovecses, Bahram Sharif-Askari, Cristobal Gonzalez-Losada, Vikash Reebye, Bríd M Ryan, Nathan W Luedtke, François E Mercier, Maureen McKeague","doi":"10.1016/j.omtn.2025.102611","DOIUrl":"10.1016/j.omtn.2025.102611","url":null,"abstract":"Acute myeloid leukemia (AML) is a highly aggressive blood cancer marked by impaired differentiation and uncontrolled proliferation of myeloid cells. This phenotype is often driven by dysregulated expression of the transcription factor C/EBPα (encoded by CEBPA), especially in high-risk subtypes with FLT3 mutations. We hypothesized that RNA activation (RNAa) of CEBPA could reduce the growth of FLT3-mutated AML, and synergize with currently approved FLT3 inhibitors, thereby offering an alternative treatment strategy for a deadly disease. Our study shows that MTL-CEBPA, a chemically modified small activating RNA encapsulated in NOV340 liposomes, selectively targets myeloid cells, boosts CEBPA expression, and promotes a non-proliferative, mature state in FLT3-mutated AML cells. Importantly, MTL-CEBPA enhances the efficacy of commonly prescribed FLT3 inhibitor, gilteritinib, both in vitro and in vivo. All together, these findings support RNAa of CEBPA as a potential adjuvant therapy for FLT3-mutated AML.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102611"},"PeriodicalIF":6.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0