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.

Kohn and colleagues provide evidence that APOBEC3A-H knockout in lentiviral vector HEK293T producer cells drastically decreases C/G→T/A mutations, leading greater than 90% reduction in total transgene mutations. In the creation of the “CHAI” HEK293T line, APOBEC3 knockout is additionally shown to be compatible with high titer vector production.

BE-PLUS-iSTOP, a DSB-free cytosine base editing strategy, precisely installs premature stop codons in HPV18 E6 and E7 oncogenes, restoring p53 and Rb tumor suppressor activity. This approach efficiently suppresses malignant phenotypes in HPV18-positive cervical cancer cells in vitro and inhibits tumor growth in vivo, with no overt systemic toxicity.

The tumor burden in bladder cancer is reduced by alpha1-oleate, which kills tumor cells and triggers rapid tumor cell shedding, by targeting multiple cell adhesion systems. Combined clinical, molecular and imaging technologies reveal broad inhibition of focal adhesions, tight junctions and adherens junctions, through a unique mechanism disrupting tumor architecture.

Since its first approval in 2017, adoptive transfer of chimeric antigen receptor (CAR)-T cells has evolved rapidly as a highly effective personalized treatment for patients with cancer. However, despite a plethora of preclinical and clinical studies, success and significant progress mainly remained restricted to hematological malignancies. Indeed, nearly a decade passed before China approved the world’s first CAR T cell product to treat solid tumors in September 2026.1 In clinical practice, tumor heterogeneity, antigen escape, and the immunosuppressive tumor microenvironment (TME), together with the lack of safely druggable targets, have emerged as key challenges in successfully extending CAR T’s potential beyond blood cancers.

The capless self-amplifying mRNA (CLsamRNA) platform recently reported by Kim et al.1 in this issue of Molecular Therapy represents the latest advance in the remarkable development of protein-coding RNAs as active pharmaceutical ingredients (APIs) for vaccines and therapeutics. The rationale for using RNA as an API has long been recognized, with evidence that in-vitro-transcribed RNA can direct protein translation reported as early as 19892 and 1990.3 Initially, clinical translation of this technology was hampered by inefficient delivery of RNA, its instability, and the tendency for exogenous RNA to provoke unwanted inflammatory responses.

Despite decades of research, glioblastoma (GBM) remains one of the most lethal human cancers. As one of the most common malignant brain tumors in adults, GBM frequently recurs despite maximal surgical resection followed by radiotherapy and temozolomide (TMZ) treatment. This persistence is widely believed to be due to a subpopulation of GBM stem cells (GSCs) capable of surviving conventional radiotherapy and pharmacological treatments to continue tumor growth.1 In this issue of Molecular Therapy, Barbieri et al.

Retinoblastoma resists immune attack in part through PD-L1. Yuti and colleagues show that GD2-CAR T cells engineered to secrete a PD-L1–blocking antibody fragment strip PD-L1 from tumor cells during contact, preventing the checkpoint upregulation that conventional CAR-T cells provoke, and remain active against tumors with low antigen density.

Yamamoto and colleagues demonstrate that DNA oligonucleotides encoding suppressor tRNA sequences are transcribed by RNA polymerase III without an exogenous promoter, enabling premature termination codon readthrough in cultured cells. This DNA-based approach provides a novel platform for suppressor tRNA therapeutics to treat nonsense mutations.

Durable liver-directed gene therapy with adeno-associated viral (AAV) vectors has proven difficult to achieve in patients with the bleeding disorder hemophilia A (coagulation factor VIII [FVIII] deficiency).1 Liver toxicity signified by liver enzyme elevations has occurred in as many as 87% of individuals in the first year. Cytotoxic T cell responses against the AAV5 capsid may occur but are unlikely to tell the entire story, as liver enzymes continued to rise in years 2–5 after dosing in 24%–40% of valoctocogene roxaparvovec phase 3 trial participants, while transgene expression declined year to year in most individuals.

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Wan and colleagues report that overcoming antigen heterogeneity in pancreatic cancer requires not only dual targeting but optimized CAR design. An asymmetric dual CAR (MSLN.BBz/NKG2D.28) enhances T-cell function, persistence, and tumor control, offering a promising strategy to improve CAR-T efficacy in solid tumors such as pancreatic cancer.

This study developed DNA aptamers targeting the SARS-CoV-2 envelope (E) protein transmembrane domain, aiming to inhibit E–E oligomerization required for viroporin formation. Apt-E-36-3 demonstrated nanomolar binding affinity, stable molecular interactions, inhibition of E protein self-association, and successful intracellular delivery, highlighting its potential as a novel antiviral therapeutic candidate.

Raghava and colleagues present AptViralDB, a manually curated repository of 1,768 experimentally verified antiviral aptamers covering 40 viral species. By integrating sequence, functional, and structural data with search, browsing, and knowledge-graph tools, the database facilitates the identification and comparison of nucleic-acid aptamers for antiviral treatments, diagnostics, and biosensors.

Molecular Therapy Oncology has released a new special collection, Advancements in Pediatric Cancer Therapy. Listen in as guest editor Nirali Shah and Editor-in-Chief Timothy Cripe discuss articles in this special collection, which covers the history, current landscape, and future direction of pediatric cancer therapy. Music: 'Electric Dreams' by Scott Buckley - released under CC-BY 4.0. www.scottbuckley.com.au

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In this study, Carvalho and colleagues demonstrate for the first time the efficacy of a novel AAV-based gene therapy for KCNV2 retinopathy. The data presented confirms restoration of visual function, gene and protein expression in a mouse model of the disease and protein expression in patient retinal organoids after treatment.

Transient p38 MAPK inhibition improves the fitness and functionality of CRISPR-Cas9-edited human HSPCs while maintaining a favorable genomic safety profile across complementary in vitro and in vivo assays, supporting its potential integration into therapeutic genome-editing workflows.

This review discusses emerging epigenome-editing strategies to restore maternal 15q11-q13 gene expression in Prader-Willi syndrome. It examines key translational challenges, validation in adquate disease models, avoidance of UBE3A dysregulation, and efficient brain-wide delivery of therapeutic tools, while highlighting novel targets for future therapeutic development.

LNP-formulated dbDNA vaccines generated durable functional antibody responses and stronger CD4+/CD8+ T cell immunity than matched mRNA vaccines in non-human primates. These responses were achieved at low dose and accompanied by distinct innate immune activation, supporting dbDNA as a potent synthetic nucleic acid vaccine platform.

pSIM, a next-generation, platform-based, antibody-free MS in vitro potency assay enables potency assessment across various mRNA molecules, supports multivalent formulations, quantifies stability-related potency loss, and correlates with in vivo neutralizing antibody responses, providing an applicable approach for mRNA product release and stability testing in QC laboratories.

Catestatin (CST), a Chromogranin A-derived peptide, is reduced across human tauopathies and Alzheimer’s disease. CST supplementation suppresses adrenergic cAMP–PKA signaling, reduces tau phosphorylation, aggregation, neuroinflammation, and amyloid burden, while improving cognition and motor function. These findings identify CST as a multimodal therapeutic candidate for neurodegenerative proteinopathies.

Artificial intelligence (AI) and machine learning (ML) are reshaping precision medicine, moving drug development from empirical trial-and-error toward rational, predictive engineering. In this collection of papers published in Molecular Therapy Nucleic Acids (MTNA), we highlight computational platforms, multi-scale biophysical models, and deep learning algorithms accelerating oligonucleotide discovery, delivery vector optimization, and disease biology decoding.

Astrocyte-targeted genome editing offers a potential one-time therapeutic strategy for Alexander disease. By optimizing AAV delivery and CRISPR/Cas9-mediated Gfap disruption, we reduce key pathological hallmarks while defining efficacy and genomic safety parameters that support the future development of astrocyte-directed therapies for leukodystrophies.

Tsai, Liu, and colleagues engineer CasNano, an ultracompact 400-amino-acid CRISPR-Cas12f from Blautia lenta. Its GC-rich CCN PAM provides access to CpG-dense regulatory elements that are inaccessible to other miniature Cas systems, and dCasNano fusions support transcriptional activation, targeted methylation, and demethylation within single-AAV cargo limits

Tian, Nikan, and colleagues report Clone F-Hprt, an IGF1R-targeted antibody–siRNA conjugate designed to expand oligonucleotide delivery beyond the liver. Local and systemic administration produced Hprt knockdown in CNS and selected peripheral tissues, supporting IGF1R as a complementary BBB shuttle receptor.