The development of versatile vaccine platforms is critical for confronting diverse threats, ranging from infectious diseases to cancer. While existing viral vectors, such as adenovirus (ADV) and vaccinia virus (VACV), represent promising strategies with their distinct advantages, challenges, including pre-existing immunity in human populations and the complexity of their proteomes, highlight the need for novel vector alternatives. Against this backdrop, severe fever with thrombocytopenia syndrome virus (SFTSV)—an emerging pathogenic arbovirus—represents both a serious public health challenge and, as revealed in this issue of Molecular Therapy by Ro et al., a surprising source for a novel solution.

Multiple deaths occurred in high-dose systemic AAV gene therapy of Duchenne muscular dystrophy and other diseases. Duan and Herzog review the clinical and laboratory findings of the fatality cases and explore underlying mechanisms and mitigating strategies.

COVID-19 vaccines brought mRNA lipid nanoparticles (LNPs) into the global spotlight, and this technology is now extending into cancer therapies.1,2,3 Although many improvements have been made to deliver LNPs to specific organs, tissues, and cells, off-target delivery remains evident. In LNP-based cancer therapies, delivering the mRNA-encoding proteins and expressing them only in target cancer cells is crucial to minimize off-target toxicity and improve clinical translation.

Chimeric antigen receptor (CAR)-presenting T cells are genetically engineered T cells that present a molecule on their surface, which, upon specific recognition of a tumor antigen, induces T cell signaling and activation followed by CAR T cell-mediated lysis of the cancer cell. This approach has dramatically improved the treatment of hematological tumors, in particular, B cell malignancies.1 Unfortunately, current approved CAR T cell therapies show multiple limitations: (1) low-level antigen expression on the cancer cells might lead to insufficient CAR T cell activity (Figure 1A); (2) CAR T cell selection pressure might enforce antigen loss or downregulation on cancer cells and thus result in escape variants that drive patient relapse (Figure 1A); (3) a single or even bispecific antigen recognition CAR (dual, tandem, or sequential CAR T cell approaches; Figure 1B) is often inefficient or not selective enough to kill tumor cells, e.g., solid tumors; and (4) CAR T cell therapy is a personalized medicine, with each patient requiring infusion of CAR-modified autologous T cells, a costly, time-consuming process that prevents treatment shortly after diagnosis.

Proinflammatory innate immune activation by unmodified mRNA is a limitation, which mandates mRNA-nucleoside modification across applications. However, Drzeniek and colleagues reveal that it is absent in cultured T lymphocytes. This eliminates the risk of inflammatory side effects and functional impairment in mRNA-engineered T cells, such as transient CAR-T cell therapy.

Major depressive disorders (MDDs) continue to impose a substantial global health burden, yet the mainstream therapeutic approach has remained largely anchored in monoaminergic mechanisms.1 While the field witnesses the rapid development of ketamine-based therapeutic targets, recent evidence also implicates impaired GABAergic inhibition and disrupted Cl− homeostasis as key contributors to circuit dysfunction associated with depression.2 In this issue of Molecular Therapy, Zhao and colleagues report that extracellular vesicle (EV)-mediated delivery of bumetanide restores neuronal Cl− balance and alleviates depressive-like behaviors in male mice.

Two promising anti-cancer therapies, alphavirus-mediated Interferon-γ delivery and photodynamic therapy, were combined to treat breast cancer in a mouse breast cancer model. The combination resulted in an almost 90% reduction in tumour weights through induction of anti-tumour immune response.

Survivin, an undruggable protein overexpressed in cancer, was targeted using a cell-penetrating peptide derived from its key functional domains. This peptide disrupts survivin dimerization and interactions with partners, inhibits cancer cell proliferation, impairs mitosis, and induces apoptosis. In-vivo, it suppresses lung tumor growth and enhances anti-tumor immunity. Thus, offering a novel approach to cancer therapy.

Rivera-Torres and colleagues disabled the NRF2 gene to restore chemosensitivity in head and neck and esophageal cancer cells. They also identified two key targeting strategies: selecting specific sites to disrupt particular protein domains and inducing exon skipping. These approaches can counteract the intended effects, even with significant gene disruption.

Hu and colleagues develop SAMVIG, a self-amplifying mRNA system that generates virus-like vesicles in tumors to activate antitumor immunity. This platform consolidates oncolytic virus benefits through multi-layered immune activation, intercellular spread, and modular payload delivery while bypassing traditional viral constraints including manufacturing complexity, neutralizing antibodies, and biosafety concerns.

(Molecular Therapy 18, 936–946; May 2010)

Lentiviral vectors (LVs) that facilitate gene delivery to desired cell types have been widely used in routine laboratory research and therapeutic cell engineering. However, the lack of proper entry receptors on many cell types often results in poor gene delivery. Here, we leveraged biocompatible chemistries to establish a synthetic virus-cell interaction for enhancing virus entry. LVs are dual-pseudotyped with the G protein from vesicular stomatitis virus (VSV-G) and a chimeric envelope protein specifically recognizing a small molecule fluorescein (αFITC-Env).

Single-cell analysis reveals that disrupted OX40-OX40L co-stimulation drives CD4+ T cell dysfunction during Mycobacterium tuberculosis infection. Restoring OX40 signaling enhances IFN-γ responses and bacterial clearance through CD40-dependent pathways, defining a CD40-OX40-IFN-γ axis for host-directed therapy in tuberculosis.

Lifelong exposure to elevated levels of atherogenic lipoproteins increases the likelihood of developing atherosclerotic cardiovascular disease (ASCVD). Contemporary lipid-lowering pharmacotherapies have transformed cardiovascular prevention; however, their effectiveness is constrained by the need for lifelong treatment, highly variable adherence, and persistent residual cardiovascular risk. Human genetic studies of naturally occurring loss-of-function variants in genes regulating lipid metabolism, including ANGPTL3, demonstrate that suppression of these pathways is associated with markedly lower levels of atherogenic lipoproteins and a substantially reduced lifetime risk of ASCVD with no apparent harmful effects.

Antisense oligonucleotides targeting CFTR splicing upregulate a naturally occurring, NMD-insensitive mRNA isoform (e22 trunc), enabling partial functional rescue of CFTR in W1282X models. Combined with modulators, this strategy restores up to 25% wild-type activity, offering a novel therapeutic approach for cystic fibrosis caused by 3′ CFTR nonsense mutations.

CRISPR-MiX is a pooled-donor strategy that improves HDR in iPSCs, reducing locus effects and enabling precise, selection-free genome editing for disease modeling.

Yin and colleagues developed lipid nanoparticle mRNA vaccines encoding key house dust mite allergens. The vaccines safely rebalanced allergic immunity and markedly reduced airway inflammation in mice, highlighting mRNA-based allergen immunotherapy as a safe and standardized next-generation approach for allergen immunotherapy.

Wu and colleagues report BASIC, a virus-like particle–based platform that enables precise, large-fragment knock-in in primary human T cells without selection. This approach streamlines multiplex genome engineering and generates uniformly edited CAR-T cells with improved therapeutic potency.

CTRP1 maintains mitochondrial dynamics to promote muscle differentiation and regeneration. Muscle-specific CTRP1 loss disrupts DRP1-mediated fission, impairs oxidative metabolism, and drives glycolytic shift. Restoring CTRP1 rescues mitochondrial function and muscle differentiation, identifying CTRP1 as a potential biomarker and therapeutic target for myopathies.

Fang and colleagues identify that SLC25A1-mediated citrate export as an actionable metabolic liability. Citrate efflux sustains cytosolic Acetyl-CoA to promote histone acetylation-dependent BIRC3 transcription and stabilize MCL1. Targeting SLC25A1, alone or with BCL2 antagonists, offers a promising therapeutic strategy for MYCN-amplified neuroblastomas.

Joint analysis of RNA-seq, Ribo-seq, and CLIP-seq data lead to the discovery of high-value 5′ UTRs. Impact of 11 5′ UTRs and its 24 mutants in synthetic mRNAs is dependent on the cell model. Synthetic mRNAs with RPL18 and RPS9’s 5′ UTRs are superior in aged and high-fat diet mice.

This study develops a synthetic gene circuit that senses hyperglycemia via a conserved O-GlcNAcylation–YAP signaling axis and autonomously produces insulin or GLP-1. The circuit enhanced glucose homeostasis in diabetic mice and ameliorated hyperglycemia-induced organ damage, offering a cell-based therapeutic strategy for diabetes.

Fan and colleagues identify CD96 as a potential target for CAR T cell therapy in AML, showing that CD96-CAR T cells effectively target CD96-expressing AML cells. This approach, especially when combined with CD33-CCR, enhances cytotoxic efficacy against AML and preserves normal hematopoiesis, offering a promising immunotherapeutic strategy.

Yang and colleagues found optic nerve injury induces lipid peroxidation, inhibition of which by a key biological modulator GPX4 or chemical antioxidant liproxstatin-1 promotes significant optic nerve regeneration and RGC neuroprotection in two optic neuropathy mouse models.

Utilizing medicinal chemistry approach, Datta and colleagues discovered a SMAC mimetic compound S-016-1348, which is active against multiple solid tumors and promotes tumor cell apoptosis independent of TNF-α. Encouraging pharmacokinetic properties, comprehensive safety pharmacology and toxicity evaluations have established S-016-1348 as a safe and effective clinical candidate.