The cover image shows pumpkin spice DNA. Formulation is a key component in the success of nucleic acid delivery. Sallah et al. investigated how the addition of cucurbit[n]urils (CBs) to cationic polymers altered the profile of DNA delivery, reducing inflammation but increasing expression. Image credit: John Tregoning, Charlotte Tregoning, and Sophie Tregoning.

The new issue of #MolecularTherapy Nucleic Acids is out now. This issue features original articles on replicon #RNA vaccination, #circRNA therapeutics, mRNA-encoded BiTE cancer therapy, and more. Read it today: http://dlvr.it/TMzM2n
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Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease Caron and colleagues evaluated molecular and imaging biomarkers in response to brain mHTT reduction in YAC128 Huntington disease mice. HTT ASO treatment slowed plasma NEFL increases, and corrected striatal oligodendrocyte transcriptional dysregulation. Plasma NEFL emerged as a sensitive response biomarker, whereas imaging did not reflect treatment effects.

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Dynamic regulation of NeuroD1 expression level by a novel viral construct during astrocyte-to-neuron reprogramming Astrocyte-to-neuron reprogramming presents a viable approach for regenerative medicine. In this report, Li and colleagues characterized a novel construct incorporating the miR-124 target site that expresses the neurogenic transcription factor NeuroD1 in a dynamical fashion during the reprogramming process and generates mature neurons with an enhanced GABAergic neuronal phenotype.

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Exploring exon excision as a therapeutic intervention strategy for the future treatment of ADGRV1-associated retinitis pigmentosa This study demonstrates a structure-guided exon excision strategy for the future treatment of ADGRV1-associated retinitis pigmentosa. CRISPR-Cas9-mediated removal of adgrv1 exons 40–42 preserved retinal function in zebrafish and proved feasible in human HEK293T cells. Altogether, this work highlights how structural insights can guide the design of effective treatment strategies.

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Measles and Rubella: From Global Health Challenges to Advancements in Molecular Diagnostics in the Elimination Era Measles and rubella cases surge globally despite vaccination efforts, with diagnostic limitations hindering elimination goals. This review examines the evolution from conventional serology to cutting-edge molecular technologies, including CRISPR-Cas, digital PCR, and next-generation sequencing. While emerging platforms offer enhanced sensitivity and point-of-care potential, bridging implementation gaps remains critical for global elimination.

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Development of a Novel Ionizable Lipid-Based mRNA Vaccine for Broad Protection Against Streptococcus pneumoniae Shi Xu and colleagues report a novel ionizable lipid-based LNP system that exhibits high mRNA delivery efficiency and develop a phylactic mRNA vaccine providing cross-protection against multiple serotypes of Streptococcus pneumoniae. This work advances the development of mRNA vaccine for combating bacterial infections.

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The circITSN1/eIF4A3/Itsn1 axis, a potential new molecular entry point for managing postoperative cognitive dysfunction Postoperative cognitive dysfunction (POCD) is the impairment of cognitive abilities in elderly patients after surgery. Among others, it encompasses neurophysiological changes and therefore impairment in the ability to learn, think, and memorize.1 While there are some patients with a risk of developing a form POCD that persists for more than a year, most cases show a reversible phenotype, with cognitive abilities being restored after several weeks or months.2 As there is no specific treatment, however, to speed up the healing process, prevention strategies are of great importance.

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Rational design and applications of piperazine and cyclohexane ionizable lipids for PKU and SSADH deficiency This manuscript has focused on the development and evaluation of piperazine and cyclohexane head based ionizable lipids for mRNA delivery, highlighting significant implications in mRNA-based therapeutics; phenylketonuria (PKU) and succinic semialdehyde dehydrogenase (SSADH) deficiency

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Single Cell Multi-Omics Data Reveals Heterogeneity in Liver Tissue Microenvironment Induced by Hypertension This study uncovers a hypertension-associated hepatocyte subpopulation and identifies key gene markers and cis-regulatory elements. These findings illuminate how hypertension reshapes the liver microenvironment, offering potential early indicators and therapeutic targets for hypertension-induced liver damage.

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Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease Piezo1, a mechanosensitive Ca2+ channel, plays pivotal roles in liver diseases by regulating fibrosis, hepatocellular carcinoma, and iron metabolism. This review summarizes its expression, functions, and therapeutic potential, highlighting key mechanisms and gaps in current research.

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Antisense oligonucleotide-mediated upregulation of Jag1 ameliorates liver disease phenotypes in a mouse model of Alagille syndrome Antisense oligonucleotides targeting the upstream open reading frame of JAG1 mRNA enhance JAG1 protein expression and improve bile duct development and liver function in a Jag1+/- mouse model, offering a promising therapeutic strategy for Alagille Syndrome.

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mRNA vaccine based on high-frequency prevalent antigens provides broad protection against influenza B virus Weijin Huang and colleagues developed an mRNA vaccine targeting high-frequency prevalent antigens of influenza B virus (IBV). This pan-IBV vaccine induces broad neutralizing antibodies and cellular immune responses, offering complete protection against diverse IBV strains and contributing to universal influenza B vaccine development

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Advancing CRISPR with Deep Learning: A Comprehensive Review of Models and Databases Machine learning (ML) and deep learning (DL) models, especially Large Language Models (LLMs) can improve CRISPR precision, but their accuracy relies on large, well-curated databases. In This review, Alipanahi and Colleagues examine existing CRISPR datasets, highlighting their role in advancing ML/DL-based predictions for safer genome editing

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Targeting long non-coding RNA MALAT1 preserves endothelial cell integrity and protects against kidney fibrosis Loss of integrity of the capillary network is directly associated with kidney fibrosis and chronic kidney disease. Bijkerk and colleagues show that pharmacological intervention of the lncRNA Malat1 protected against fibrosis in experimental kidney injury and preserved vascular integrity, and may serve as potential treatment for chronic kidney disease

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Pharmacometric Modeling of Lipid Nanoparticle-Encapsulated mRNA Therapeutics and Vaccines: A Systematic Review This review summarizes quantitative approaches for model-informed drug development of mRNA-LNP modalities by incorporating ADME, PK/PD and mechanistic models to guide FIH dosing and clinical study design. Literature review reveals that numerous clinical studies involving mRNA-LNPs have been conducted across a range of therapeutic areas and vaccine platforms.

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Molecular Properties and Intramolecular interactions of Peptide-Conjugated Phosphorodiamidate Morpholino Oligonucleotides Barsegov, Chanda, and colleagues combined CD and viscosity measurements with MD simulations and machine learning to characterize non-canonical structures and concentration-dependent interactions in peptide-conjugated PPMOs. The results explain similarities to PMOs, peptide-enhanced uptake, and viscosity differences, enabling rational design of PPMO formulations with improved cellular delivery and solution behavior.

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Molecular treatment options for patients carrying KIAA0586 / TALPID3 variants RNA-AON-based and read-through therapies were tested in fibroblasts from Joubert Syndrome patients with KIAA0586/TALPID3 mutations. The treatments improved ciliary and PCM1 defects caused by a nonsense and deep-intronic splicing variant, highlighting potential mutation-independent / -agnostic therapeutic strategies for genetically heterogeneous disorders including ciliopathies.

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The potential and challenges of circular RNA in the development of vaccines and drugs for emerging infectious diseases This review explores the potential of circular RNA (circRNA) in vaccine and drug development for emerging infectious diseases (EIDs). It highlights circRNA's stability, immunomodulatory properties, and therapeutic promise, offering innovative solutions to overcome the limitations of traditional vaccine and drug strategies in rapidly evolving disease contexts.

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Analytical Approach for Identification and Mechanistic Insights into mRNA-Lipid Adducts Formation This study introduces a high-throughput analytical method that directly extracts mRNA and quantifies mRNA-lipid adducts from lipid nanoparticles. Mass spectrometry reveals adduct structures and reaction mechanisms previously unreported. Studies on LNP formulation optimization highlight pH's crucial role in adduct formation, offering valuable insights for mRNA therapeutic development and stability optimization.

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Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy This study uses a zebrafish model of Duchenne muscular dystrophy to identify an HDACi, SR-4370, that improves muscle structure and survival in dmd zebrafish. They show that HDACi that improve dmd zebrafish muscle also cause increased histone acetylation in zebrafish. These results underscore HDACi as promising candidates for treating DMD.

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Progress and prospect of minicircle as a minimized non-viral DNA vector in gene therapy and regenerative medicine In this study, Dormiani and colleagues provide a comprehensive review that presents the characteristics, production methods, and drawbacks of minicircles as small, episomal, non-viral DNA vectors. Additionally, the review covers several in vitro and in vivo investigations that have utilized these vectors in gene therapy and regenerative medicine.

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Transcriptomic analysis reveals lung cancer and subtype-specific alternative splicing biomarkers regulated by RNA-binding proteins Feng and colleagues generate a high-quality lung cancer transcriptome resource and identify cancer- and subtype-specific splicing biomarkers through integrative analysis. By modeling RNA-binding protein activity, they uncover critical regulators of alternative splicing with implications for cancer biology and prognosis.

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RNA Trans-splicing to Rescue β-Catenin: A Novel Approach for Treating CTNNB1-Haploinsufficiency Disorder Jerala and colleagues investigate an RNA trans-splicing strategy to correct CTNNB1 syndrome mutations and restore β-catenin expression. Using ribozymes, short antisense RNAs, and optimized promoters, they enhance trans-splicing in a split YFP reporter system, highlighting its therapeutic potential for CTNNB1 syndrome.

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MicroRNAs and Synaptic Dysfunction in Parkinson’s Disease Synaptic microRNAs (miRNAs) are emerging as significant regulators of synaptic function and dysfunction in Parkinson’s disease (PD). This review presents growing evidence linking synaptic miRNAs to PD pathology, proposes their potential as biomarkers and therapeutic interventions in the pursuit of understanding, treating, and curing this debilitating neurodegenerative disease.

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A series of precise and controllable base editors with split-TadA-8e Strategic cleavage of the TadA-8e deaminase enabled development of rapamycin-controlled split adenine base editors (sABE8e, sAYBE, seA&C-BEmax). These tools maintain on-target efficiency when induced but drastically reduce off-target effects and indels by limiting deaminase duration. This breakthrough improves the safety and precision of therapeutic base editing.

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Alterations in Mitochondrial Base Editors Enhance Targeted Editing Efficiency for Mouse Model Generation Lee and colleagues developed two enhanced mitochondrial adenine base editors, Hifi-sTALED and αnHifi-sTALED, that improve editing efficiency while maintaining minimized off-target effects. These tools successfully generated mt-Rnr1 mutant mice and revealed mitochondrial dysfunction, offering a robust platform for modeling mitochondrial diseases and studying mtDNA mutations.

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Preclinical Efficacy of Multi-targeting mRNA-based CAR T Cell Therapy in Resection Models of Glioblastoma Dagher and colleagues demonstrate that transient, multi-targeting mRNA-engineered CAR T cells, delivered after maximal glioblastoma resection, eradicate tumors in subcutaneous and orthotopic patient-derived xenograft models. This readily manufactured approach counteracts antigen heterogeneity and advances a safe, adaptable immunotherapy platform for otherwise incurable solid tumors.

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Human Opsin Restoration by Histone Methylation using Methyltransferase Fusion Protein SETD7-dCas9 SETD7-dCas9 enables targeted histone methylation to activate gene expression. By restoring medium-wavelength opsin in retinal cells, this epigenetic approach offers a mutation-independent strategy for treating Retinitis Pigmentosa, highlighting histone methylation–based gene activation as a versatile therapeutic platform.

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Nose-to-brain siRNA delivery by PEI/PPI-based nanoparticles reduces α-synuclein expression in a Parkinson’s disease mouse model Intranasal nanoparticle delivery of siRNA effectively reduces brain alpha-synuclein levels in a Parkinson’s disease mouse model, offering a non-invasive therapeutic strategy with clinical potential.

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Context dependent role of miR-486 promoting neuroregeneration of primary sensory neurons down-stream of Interleukin-6 signal transducer Kalpachidou, Kress and colleagues identify miR-486 as a miRNA promoting neuronal regeneration. Their findings uncover a novel, context-dependent role for miR-486 and identify molecular pathways involved in IL-6/gp130-induced support of peripheral nerve regenerative processes.

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