Infusion-related reactions (IRRs) can occur with AAV gene therapy. IRRs were observed in two participants who received AAV8 gene therapy and in one who received AAV9 gene therapy. AAV gene therapy IRRs may be rate-related, possibly driven by complement activation. In our studies, a slow, staged infusion mitigated additional IRRs.

Transduction efficiency is a critical determinant of CAR T-cell manufacturing quality. Analysis of 204 clinical CAR T-cell products revealed that transduction efficiency is shaped primarily by manufacturing workflows and protocol-dependent starting material composition. Higher transduction efficiency was associated with early memory-like cellular states, providing insights into optimizing CAR T-cell.

Kis and colleagues report an integrated sequential-batch IVT–oligo-dT process that links RNA synthesis and affinity capture through a shared buffer, enabling direct crude-IVT loading and flowthrough recycling. The workflow improves cap-analog utilization and raw-material efficiency while preserving functional mRNA expression across five cycles.

Immunization with a nucleoside-modified mRNA-LNP vaccine encoding the conserved malaria antigen E140 induced durable humoral immunity in mice and generated invasion-blocking antibodies against Plasmodium vivax. The results highlight E140 as a promising candidate for next-generation malaria vaccines.

With the passing of Dr. Christopher D. Porada in June 2026, Molecular Therapy lost a dedicated and highly accomplished associate editor, and the field of gene and cell therapy lost a visionary pioneer whose lifelong goal was to eliminate inherited diseases before birth so that a child could be free of disease after birth.

Blancafort and colleagues describe a non-viral polymeric system for the delivery of dCas9-KRAB silencers as ribonucleoprotein (RNP) payloads for EWSR1-FLI1 repression. They demonstrate highly efficient RNP delivery and robust silencing of EWSR1-FLI1 in both cell line and patient-derived xenografts of Ewing sarcoma, accompanied by potent anti-tumor effects.

The efficacy of vaccines remains suboptimal in many settings, underscoring the need for new strategies. Baydemir and colleagues show that modulation of acetyl-CoA metabolism reshapes metabolic and epigenetic programs underlying Bacille Calmette-Guérin-induced trained immunity, enhancing cellular innate immune responses and identifying immunometabolic targeting as a promising approach to improve vaccine efficacy.

LMNA-related congenital muscular dystrophy (L-CMD) is a devastating early-onset muscle disease caused by dysfunctional nuclear lamina. Current models fail to capture the complexity of human muscle pathology, limiting translational progress. This study overcomes this limitation by establishing a robust, human iPSC-based platform for modelling L-CMD and testing gene editing strategies.

A vasoactive intestinal peptide (VIP)-based protein carrier self-assembles with respiratory syncytial virus circular RNA vaccines for intranasal delivery, inducing systemic antibodies, mucosal IgA, and Th1-biased protection in mice. This platform offers a protein-guided strategy for respiratory mucosal RNA vaccination and broadens the application of VIP in vaccine delivery.

Red blood cell-derived extracellular vesicles (RBCEVs) provide a scalable, non-viral platform for gene therapy. High-grade RBCEVs purified using tangential flow filtration can deliver sizable plasmids and mediate sustained in vivo expression of therapeutic proteins, including factor IX and Herceptin, highlighting their potential use for safe and efficient gene therapy.

Obesity expands a pathogenic ITGA7high adipose stromal cell population that promotes fibrosis. We engineered ITGA7-targeted lipid-coated mesoporous silica nanoparticles to selectively deliver plasminogen activator inhibitor-1 small interfering RNA, suppress profibrotic signaling, and restore a healthier adipose microenvironment.

Intracranial delivery of iPSC-derived neural stem cells overexpressing SGSH restored brain enzyme activity and memory while reducing glycosaminoglycan accumulation and neuroinflammation in an immunodeficient MPS IIIA mouse model. These findings support a promising cell-based therapeutic strategy for treating MPS IIIA and related lysosomal storage disorders.

In preclinical studies, UB-VV400, an off-the-shelf, investigational lentiviral drug product, generates fully human anti-CD22 CAR T cells in vivo without the need for lymphodepletion. Activation of the synthetic rapamycin-activated cytokine receptor drives selective CAR T cell expansion and enrichment, resulting in complete tumor clearance and B cell depletion.

Sasso and colleagues leveraged organ-specific miRNAs by engineering synthetic mRNA vaccines containing miR target sites to generate a functional map of immunologically competent organs. This work lays the foundation for novel vaccines designed to target the most immunologically proficient organs. They subsequently applied this approach to de-immunize Cas9, rendering it immunologically masked.

By fusing MCM5, a subunit of the eukaryotic MCM2–7 helicase complex, to the N terminus of spCas9 (MCCas), the MCCas fusion protein enhances large-size fragment knockin via homologous recombination, reduces insertions and deletions (indels), and enables efficient large-size fragment insertions in human cells and rabbit embryos.

Latent HIV reservoirs evade both antiviral therapy and immune surveillance. Luo and colleagues develop a multifunctional fusion protein that couples reservoir reactivation with targeted immune engagement and clearance, offering a coordinated strategy to expose and eliminate persistent HIV-infected cells.

To overcome the strict packaging limits of AAV vectors, this study utilizes a triple-AAV system paired with orthogonal split inteins to reconstitute the exceptionally large LAMA2 protein. This scarless, multi-vector approach successfully rescues the dystrophic phenotype in vivo, offering a scalable platform for large-gene therapies.

Anti-thrombin anticoagulant aptamers act as dual-targeting agents by recognizing both thrombin and its precursor, prothrombin. Biophysical and structural analyses reveal a similar recognition mechanism and suggest that aptamer binding shifts prothrombin toward its open conformation, providing new insights for the rational design of next-generation anticoagulant therapeutics.

Wagner and colleagues develop BEKI (Base Editor-mediated Knock-In), a non-viral platform that combines targeted transgene insertion with simultaneous gene knockouts in a single step. BEKI-engineered CAR T cells show markedly reduced chromosomal rearrangements compared with conventional nuclease-based approaches, advancing safer manufacturing of multiplex-edited cell therapies for cancer and autoimmune diseases.

Currently no effective therapies are available for glioblastoma. Florio and colleagues identified, via computational screening, triamterene as a CLIC1 blocker that suppresses human glioblastoma stem cell proliferation, invasiveness, and tumor growth. Triamterene also enhances temozolomide and radio-chemotherapy efficacy, making it a repurposed therapeutic candidate for glioblastoma treatment in future clinical applications.