Dolgusheva and colleagues present Xelari, a structure-based pipeline that designs DNA and RNA aptamers without SELEX. Candidate generation takes hours per target. Four designed DNA aptamers were experimentally functional in two independent assay settings, supporting structure-based design as a complement to, not a replacement for, experimental selection.

Gupta and colleagues demonstrate that AAV9-mediated overexpression of the lncRNA Lockd restores cardiac function in non-regenerative neonatal hearts following isoproterenol injury by promoting cardiomyocyte proliferation. Mechanistically, Lockd stabilizes ENO1, enhancing β-catenin and Myc signaling to drive cardiac regeneration.

Yamazaki and colleagues demonstrated that an orthogonal spectroscopic strategy, utilizing circular dichroism (CD), Raman, and fourier-transform infrared (FT-IR) analyses, enables systematic evaluation of concentration-dependent higher-order structure changes in nucleic acid therapeutics. This provides a practical platform for the characterization and quality assessment of nucleic acid-based drugs relevant to formulation.

Systemic, RPE-targeted AAV-tyrosinase gene replacement restored widespread ocular pigmentation in an oculocutaneous albinism type 1 (OCA1) mouse model. AAV-mediated pigment restoration reduced photophobic behavior in treated mice, establishing a functional therapeutic benefit for tyrosinase replacement therapy and supporting future clinical gene therapy investigation for albinism.

Cell therapies including CAR-T, CAR-NK, and engineered mesenchymal stem cells offer promising strategies for gastrointestinal cancers. This review covers manufacturing workflows, antitumor mechanisms, clinical trials, and tumor microenvironment challenges, while highlighting future directions such as in vivo CAR generation, logic-gated circuits, AI-guided design, and next-generation gene editing.

Afroj and colleagues demonstrate that viral detection by RNA-seq is strongly influenced by RNA extraction, library preparation, indexing strategy, and bioinformatics workflow. Using multiple matrices and viral reference materials, they identify key factors affecting assay sensitivity and specificity and provide considerations for qualification of RNA-Seq based adventitious virus detection assays

Lu Q. Le reports equipment, drugs, or supplies was provided by SpringWorks Therapeutics. Lei Chen reports a relationship with SpringWorks Therapeutics that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Reduced miR-181a expression was associated with greater histopathological severity in human tendinopathy. In tendinopathic tenocytes, miR-181a gene transfer attenuated IL-1β-induced cellular senescence and apoptosis, accompanied by modulation of TAB2/NF-κB and TGF-βRI/Smad2 signaling, supporting miR-181a as a potential therapeutic strategy for tendinopathy.

Few AAV vectors integrate lung tropism, scalable production, and immune distinctiveness. Ivan and colleagues show that Bovine AAV combines these properties, enabling systemic lung-directed transduction, efficient entry into pulmonary microvascular endothelium, and reduced cross-neutralization by prevalent serotypes, supporting its development for pulmonary gene therapy and rational capsid engineering programs.

APN401 combines transient CBL-B silencing in autologous PBMCs with rapid point-of-care manufacturing. In two Phase I studies, repeated APN401 administration was feasible and well tolerated. Exploratory analyses identified systemic immune modulation and T-cell clonal expansion, supporting further investigation of transient intracellular checkpoint modulation in solid tumors

Artificial intelligence is rapidly transforming every stage of precision medicine, from discovering disease biomarkers to engineering targeted delivery…

This episode, hosted by Daniel Stone, Associate Editor-in-Chief of Molecular Therapy Advances, focuses on the article, Normothermic perfusion of human…

Lipid nanoparticles (LNPs) are attractive approach for mRNA and CRISPR delivery but exhibit cell and tissue-specific tropism. Here, the authors demonstrate that substitution of lipid types in LNPs significantly enhances cargo mRNA translation and achieves successful CRISPR gene editing in vascular endothelial cells in 2D and 3D-microfluidic systems.

RNA-targeted therapeutics can achieve substantial hepatitis B surface antigen reduction, but durable functional cure depends on viral reservoirs, host immunity, delivery, and patient selection. This review critically compares siRNA, antisense oligonucleotide, miRNA, and CRISPR platforms and proposes biomarker-guided, staged treatment strategies integrating antigen reduction with immune consolidation.

Reynolds and colleagues developed a novel therapy for hepatocellular carcinoma. A rare variant in the oncogene NELFE induces alternative splicing reducing NELFE expression. Targeted delivery of NELFE morpholinos, a functional biomimetic of the variant, through ultrasound targeted microbubble destruction improved survival in vivo as NELFE knockdown reduces cancer cell phenotypes.

Ghosh and colleagues report a genome editing strategy for upregulating utrophin. MyoAAV-based editing of the Utrn 3′UTR led to utrophin upregulation, improved muscle function, and amelioration of dystrophic muscle histopathology in mdx mice. This approach represents a promising therapeutic strategy applicable for all DMD patients, irrespective of their mutation status.

Inherited retinal diseases are among the leading causes of blindness and collectively affect over 5.5 million individuals worldwide. The eye has emerged as an attractive target organ for gene and RNA therapeutics because of its small size, accessibility, and relative immune privilege. Following the approval of voretigene neparvovec (Luxturna), the first in vivo gene therapy, many efforts are ongoing to develop therapies to restore or stabilize vision.1 A major challenge, however, is tremendous genetic heterogeneity, with thousands of pathogenic variants identified in over 500 disease genes.

The K78A mutated PD-1 receptor-based CAR led to PD-L1 interaction loss. Anti-PD-1 mAbs administration activated mRNA-based CARs in an antigen-independent manner. Addition of a hinge domain improved functionality. Primary T-cell validation demonstrated enhanced tumor killing when PD-1 CARs were combined with tumor-targeting TCRs, indicating an additive therapeutic effect in vitro.

The rapid clinical deployment of mRNA-lipid nanoparticle (LNP) vaccines during the COVID-19 pandemic has firmly established this platform as a cornerstone of modern therapeutics, with applications extending beyond vaccination to include gene replacement and CRISPR-Cas9 genome editing. Yet fundamental questions persist regarding the relationship between mRNA biodistribution, tissue-specific translation, and immunological outcomes—questions with profound implications for both vaccine design and gene therapy safety.

Cryo-thermal therapy combined with anti-PD-1 reprograms the TME, converting “cold” tumors to “hot” by uniquely activating a CCL5-mediated T cell recruitment pathway. IFN-γ and TNF-α synergistically enhance myeloid CCL5 production via a novel feedback loop, establishing an effective strategy to overcome anti-PD-1 resistance with therapeutic potential.

Allogeneic NK-cell therapies show a favorable early safety profile but variable clinical activity. This review advances receptor-ligand matching as a precision framework that integrates donor KIR/HLA immunogenetics, NK-cell education, and tumor ligand landscapes. Incorporating these biomarkers into donor selection and trial design could improve the interpretability, reproducibility and clinical development of NK-cell cancer therapies.

Janc and her colleague developed digital PCR assays that uncover the quantity and integrity of unwanted DNA contaminants in recombinant AAV samples. Their findings offer improved analytical tools for safer, higher-quality gene therapy development.

BL828, a new spliceosome inhibitor, enhances tumor antigen presentation and T cell-mediated immunity, drives potent anti-tumor responses in pediatric mouse models, and highlights splicing modulation as a promising immunotherapy strategy for childhood cancers.

Shih and colleagues reveal a miR-3156-3p–potassium channel axis that regulates calcium-dependent viral egress during enterovirus D68 (EV-D68) infection. Antagonizing miR-3156-3p reduces viral release and virus-associated acute flaccid paralysis in mice, highlighting microRNA modulation as a potential nucleic-acid-based prophylactic strategy to disrupt non-lytic viral dissemination.

Adeno-associated virus (AAV) gene therapy has shown efficacy in multiple monogenic diseases but continues to face a significant barrier: pre-existing anti-AAV neutralizing antibodies (NAbs) in patient plasma. Following systemic administration of AAV gene therapy, circulating NAbs can impede gene transfer, pose safety risks, and preclude vector redosing. At present, there is a dearth of effective strategies to overcome the barriers posed by NAbs. In a new article in Molecular Therapy Advances, Xu et al.

Liu and colleagues identify antigen shedding as a key barrier to CAR-macrophage therapy. By targeting a non-shed epitope of tumor antigen, they overcome this limitation, achieving tumor clearance and durable systemic immunity in immunocompetent transgenic mice. The work established epitope selection as a critical design principle for CAR-M therapies.

An oncolytic virus encoding EphrinA2 elicits an improved humoral response to the expressed antigen that is CD4 T cell dependent and capable of glioma activity. Together with our prior CD8 T cell results, this suggests that OV-antigen expression utilizes all arms of the adaptive immune response to mediate glioma therapy.

This review examines gene therapy for cancer, covering viral, bacterial, physical, and chemical delivery platforms alongside suicide gene therapy and immunomodulatory strategies, with emphasis on CAR-T cell therapy. Recent regulatory advances and next-generation vectors are highlighted, alongside future directions including genome editing and improved accessibility for durable clinical remission.

Lee and colleagues developed a TadA8e-dBhCas12b adenine base editor based on a catalytically inactive Cas12b module that recognizes thymine-rich PAMs and enables precise A-to-G conversion with minimal indel formation. Engineering of the RuvC domain and DNA-binding architecture modulated editing-window profiles, expanding the available base-editing toolkit for human cells.

Wang and colleagues identify that microRNA-21 drives inflammatory bowel disease by disrupting the balance between pro-inflammatory Th17 and regulatory T cells. miR-21 directly targets Smad7 and Ski, activating a key signaling pathway. This work reveals a new therapeutic target, suggesting that inhibiting miR-21 alleviates colitis in mice.

Zhu, Schaefer and colleagues developed a screening platform using zebrafish larvae to efficiently screen multiple candidate “tumor-targeting” oligonucleotides. This novel platform addresses the bottle neck caused by time and cost restraints, that occurs when transitioning from in vitro screening to in vivo testing using murine models

Systemic intravenous delivery of Lentiviral vector could reduce cost and improve accessibility of gene therapies, but immunogenicity is a major barrier to safety and efficacy. Keating and colleagues outline elements of the immune system that compromise in vivo delivery, and highlight approaches developed to overcome these.

An integrated analytical strategy combining CDMS and native digestion was used to study AAV stability under thermal stress, revealing diverse degradation products arising from cooperative DNA ejection and VP1u externalization. Tethering between ejected DNA and externalized viral protein promoted large aggregate formation, which was confirmed by native enzyme treatment.

Yang and colleagues revealed that the calcineurin subunit PPP3CA modulates TAM plasticity via NF-κB signaling in lung cancer; its deficiency fosters pro-tumor M2 polarization and impaired anti-tumor immunity, uncovering a critical target to reshape the tumor microenvironment and guide precise immunotherapeutic strategies.

Viral vector-based gene therapy is a transformative therapeutic approach for rare genetic diseases. The fundamental concept is to replace a transcript and/or protein that is reduced or lost due to underlying mutation(s) in the corresponding gene. Seminal examples that demonstrate the power and potential of this therapeutic strategy include AAV9-SMN1 gene therapy (trade name Zolgensma) for spinal muscular atrophy and AAV2-RPE65 (trade name Luxturna) for inherited blindness. Both treatments dramatically alter disease trajectory and provide transformative benefit for affected patients who receive it.

(Molecular Therapy 34, 3417–3435; June 2026)

Lipid nanoparticle–delivered DNA triggers cGAS-dependent innate immunity, limiting transgene persistence and causing hepatotoxicity. Sun and colleagues identify a cGAS–interferon–TREX1 axis that degrades therapeutic DNA and a parallel MyD88-driven inflammatory pathway. Prophylactic dexamethasone or JAK inhibition mitigates toxicity, revealing immunomodulation as a strategy to unlock DNA-based gene therapy.

(Molecular Therapy 34, 5697–5709; October 2026)

Kontogiannis and colleagues integrate a quadruplex digital PCR assay with long-read sequencing to support comprehensive and standardized characterization of genome integrity and purity rAAV9.

Curtis and colleagues engineer a silencing-resistant, selectable CRISPRa platform in primary CAR T cells, enabling genome-wide survival-based screens that nominate endogenous genes to enhance CAR T cell fitness.

Nucleic acid therapeutics induce a conserved early innate inflammatory response, driven mainly by nucleic acid sensing, that limits nucleic-acid therapeutics' safety and dosing. Modulating this response reduces reactogenicity without impairing immunity, gene expression, or delivery, offering a strategy to improve the safety and efficacy of mRNA vaccines, viral vectors, and genome editing.

Gene and stem cell therapies in Huntington’s Disease are fraught with ethical complexity. Genetic discrimination, surgical placebos, therapeutic misconception, justice and equity all need careful consideration by researchers and funders. This paper provides those involved in advanced therapies research a comprehensive overview of the ethical issues.

(Mol. Ther. 29, 1199–1213, March 2021)

Yan and his colleagues review how RNA cargo packaged in extracellular vesicles remodels the tumor immune microenvironment. They discuss technical challenges limiting biomarker utility, compare nucleic-acid loading strategies for engineered vesicles, and outline major translational obstacles hindering clinical adoption of EV-nucleic-acid-based personalized cancer immunotherapy.

Dalgaard and colleagues combined systematic literature review with database-driven analyses to generate an annotated resource of plasma membrane proteins in human skeletal muscle. This curated framework identifies candidate targets and supports the development of next-generation delivery platforms for RNA therapeutics and other modalities across diverse muscle-related diseases.

He and colleagues describe the structure-based design of HIV fusion-inhibitory lipopeptide LP-101, which exhibits dramatically improved activity against resistant mutant viruses and high therapeutic efficacies in both HIV-infected humanized mice and SIV-infected rhesus macaques.