Żak and colleagues present cSMRTS (cancer-Selective modRNA Translation System), which enables tumor-selective expression of therapeutic mRNA following systemic delivery. By redirecting the targeting strategy from LNPs to the engineered mRNA payload, cSMRTS overcomes the hepatotropic bias of LNPs and establishes a versatile framework for next-generation targeted mRNA therapeutics.

Kaufman and colleagues study the utility of optical genome mapping as an unbiased, genome wide, methodology for detecting genomic structural variants upon genetic engineering. The study indicates that OGM can serve as a valuable QC step, aiding the evaluation, and selection, of edited cells for further research and therapeutic applications.

Engineered mesenchymal stromal cells expressing ACE2 (MSCACE2) integrate receptor-mediated viral trapping with immunomodulation to combat SARS-CoV-2–induced ARDS. MSCACE2 reduced viral burden, preserved epithelial–endothelial integrity, and reprogrammed proteomic pathways, demonstrating a dual-function cell therapy platform with translational potential across both early and established infection stages.

Cystic fibrosis (CF) is a progressive, life-threatening genetic disorder that impacts about 100,000 people worldwide. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which is inherited in an autosomal recessive manner.1 A defective CFTR protein decreases chloride efflux while increasing sodium absorption across epithelial cells. This ionic imbalance leads to the dehydration of the epithelial surface, resulting in the accumulation of thick mucus. CF affects multiple organs in the body, including the lungs, pancreatic ducts, the biliary tract in the liver, the intestines, and the reproductive system.

von Willebrand disease (VWD), the most common inherited bleeding disorder, results from quantitative or qualitative defects in von Willebrand factor (VWF).1 Among the qualitative forms, type 2A and its IIC variant are defined by the loss of high-molecular-weight VWF multimers essential for platelet adhesion and aggregation.2 These defects typically arise from mutations in the VWF propeptide (VWFpp) domain that impair VWF multimer assembly and Weibel-Palade body (WPB) formation.3 Conventional therapy relies on plasma-derived or recombinant VWF infusions, which provide transient hemostatic benefit but do not correct the underlying biosynthetic defect.

In their recent publication in Molecular Therapy, Velasco-de-Andrés et al.1 report on a novel approach to treating invasive fungal infections (IFIs) using cord blood-derived natural killer (NK) cells engineered to express chimeric antigen receptors (CARs) utilizing the glycoprotein CD5 as a targeting moiety, based on the natural β-glucan-binding ability of CD5. β-Glucans are a class of polysaccharides found in the cell wall of most fungi and represent a broad, specific, and conserved target for antifungal therapies.

Chimeric antigen receptor (CAR)-T cell therapy (CAR-T) has achieved remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including glioblastoma (GBM), is significantly hampered by the complexity of autologous cell manufacturing, tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and adverse effects such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome.1 In this issue of Molecular Therapy, Li et al.

Grubor, Henry and colleagues investigated events preceding dorsal root ganglion (DRG) toxicity following intra-CSF administration of adeno-associated virus (AAV) gene therapy in non-human primates. They identified an immune response prior to neuronal degeneration and were able to mitigate toxicity with a novel immunosuppression regimen.

Myotonic dystrophy type 1 (DM1) exemplifies the challenge of translating molecular insights into effective gene therapies. This multisystemic disorder, the most common adult-onset muscular dystrophy, results from a CTG triplet-repeat expansion in the 3′ untranslated region (UTR) of the DMPK gene, which produces toxic RNA hairpins that sequester RNA-binding proteins and disrupt normal splicing regulation. Despite decades of research aimed at clarifying this cascade, there is still no disease-modifying treatment.

Since the first US Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR)-T cell therapies in 2017, over 34,000 patients have received autologous CAR-T cells in the United States.1 By the start of 2024, 22 cases of T cell cancers occurring after treatment with CAR-T cell products had been reported to the FDA, with most occurring within 2 years after CAR-T cell administration. Three of these cases reported detection of the CAR transgene in the malignant clone, suggesting a causal link between the CAR and malignant transformation.

Direct intraparenchymal AAV delivery can be enhanced by engineering the capsid’s glycan binding profile. A single amino acid substitution of AAV5 reduces sialic acid dependency, rendering the modified capsid more potent and showing improved biodistribution in small and large animal models.

Lipid nanoparticle formulation delivering dual-functional CpG-siSTAT3 to B cell lymphoma and associated myeloid cells achieves enhanced drainage to tumor-draining lymph nodes, broadened therapeutic window through improved potency at lower doses, and activation of dendritic and tumor infiltrating T cells, offering an effective strategy to boost antitumor immunity.

Aberrant N6-methyladenosine (m6A) modification has emerged as a hallmark of hematologic malignancies, with the writer enzyme METTL3 playing a pivotal role in RNA metabolism and leukemogenesis.1,2 However, the post-translational mechanisms governing METTL3 stability and function remain poorly understood. In a recent study published in Molecular Therapy, Gou and colleagues uncover a key metabolic-epitranscriptomic interface in which O-GlcNAcylation at Ser184 and Ser243 stabilizes METTL3 and enhances its oncogenic m6A activity in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

In 1990, two seminal studies introduced a novel method, systematic evolution of ligands by exponential enrichment (SELEX), to discover and isolate…

Chadarevian and colleagues demonstrate that CSF1R-G793A mice exhibit broad CSF1Rinhibitor resistance, enabling efficient microglia replacement following intraparenchymal, intracisternal, or bone marrow transplantation. Collectively, these results indicate that CSF1R-G793A mice provide a powerful new tool to investigate microglia replacement strategies that leverage the therapeutic potential of inhibitor-resistant iPSC microglia for neurodegenerative disease.

Microglia replacement holds broad therapeutic promise. Applying a transgenic, CSF1R inhibitor-resistant mouse line, Lombroso and colleagues introduce a new strategy for microglia replacement by intravenous delivery of microglial surrogates that enter and colonize the microglia-depleted brain at high efficiency and reduced toxicity compared to traditional hematopoietic stem cell transplantation.

Xing and colleagues introduce DeepHEM, an innovative deep domain-adversarial learning framework specifically for identifying essential human miRNAs, to realize cross-species knowledge transfer. A comprehensive multi-modal feature extractor is developed to capture the abundant feature representations of miRNAs and a multi-loss optimization module is constructed to align across-domains feature distributions.

The authors describe an AAV gene therapy to reduce α-synuclein pathology in Parkinson’s Disease (PD). They demonstrate that 50% reduction of alpha-synuclein mitigates the spread of pathology in the rodent PFF model of PD. Human-specific sequences were screened in vitro and in vivo, identifying therapeutic candidates with high potency, efficient processing and low-off targeting profiles.

The upregulation of METTL5-mediated rRNA m6A modification promotes HCC recurrence under heat stress post-RFA through fatty acid metabolic remodeling of peroxisomal-mitochondria interaction. Inhibition of the METTL5-PEX16 axis provides a novel strategy to prevent tumor recurrence and progression post-RFA.

Imaging of gene expression remains a critical challenge in gene therapy. Here the authors report an in vivo demonstration of a genetically encoded MRI reporter expressed from a recombinant adeno-associated virus (rAAV) to detect transgene expression. Mice were systemically administered rAAV encoding superCESTide with dose-dependent MRI signal enhancement in the liver.

Xiao-Ran Jiang and colleagues review how synthetic biology reprograms bacteria into programmable living therapeutics. These engineered platforms achieve organ-specific disease targeting and cancer therapy through tumor colonization and therapeutic payload delivery, utilizing precision genetic toolkits. This technological integration advances medical interventions beyond conventional approaches, offering versatile clinical solutions.

Fortuna and colleagues show that PHP.eB, an engineered AAV9 variant, efficiently transduces the primate CNS after intracerebroventricular administration. This work reveals a previously uncharacterized biodistribution profile of PHP.eB in large mammals, providing critical insights into its potential and limitations for CNS-directed gene therapy.

CRISPR-based engineering of TCR-T cells remains limited by low editing efficiency and genomic instability. This study demonstrates a non-viral platform that couples precise genome targeting with selective enrichment, enabling safe and efficient generation of therapeutic T cells for cancer immunotherapy.

This study reports an innovative translational strategy that converts conventional T cells into potent, persistent, and sustained immune-regulatory αp-T cells by equipping them with immunomodulatory molecules IFN-α2 and PD-L1. These αp-T cells function through a synergistic regulatory loop to suppress GVHD while preserving anti-leukemia activity of allogeneic T cells.

Five cancer antigen-specific NIR-PIT agents targeting EGFR, Her2, FOLR1, TROP2, and TF were developed to selectively kill ovarian cancer cells. These agents induced immunogenic cell death and promoted dendritic cell maturation, demonstrating strong potential for immune-activating ovarian cancer therapy.