He and colleagues developed a transient, non-gene-editing platform for off-the-shelf allogeneic TCR-T therapy. By conferring tacrolimus resistance characteristics to IL-2/4/7 expanded TCR-T cells that display reduced alloreactivity, He et al. provided a proof-of-concept for an allogeneic TCR-T therapy approach that addresses both manufacturability, and unwanted graft and host alloreactivity concerns.

Zhang and colleagues engineered the poly(A) tail as a programmable regulatory element, showing that embedding cell-type-specific microRNA target sites directly within it confers robust, position-dependent silencing in off-target tissues while preserving activity in target cells. This strategy offers a new modular tool to enhance mRNA therapeutic safety and precision.

Gene therapy is transforming hereditary hematological disorders. This review summarizes approved gene addition, editing, and silencing strategies for sickle cell disease, thalassemia, and hemophilia, highlights curative potential, and discusses remaining challenges such as immune responses, cost, and accessibility

(Molecular Therapy 31, 1596–1614; June 2023)

Yuan and colleagues demonstrate that inhaled biodegradable nanosilica activates an alveolar macrophage–NK axis, triggering an IL-12/15/18 triad that programs memory-like NK cells. This non-fibrotic, cell-free strategy suppresses melanoma growth, prevents postsurgical recurrence, and synergizes with anti-PD-1, establishing a robust framework for in vivo NK cell immunotherapy.

Zhang and colleagues reveal that GPX4 serves as a critical regulator of NRF2-mediated otoprotection against aminoglycoside-induced hair cell injury. Their findings identify a GPX4-dependent antioxidant mechanism that enables therapeutic activation of NRF2 and provides new insights into strategies for preventing drug-induced hearing loss.

Ouabain triggers cochlear spiral ganglion neuron (SGN) ferroptosis and hearing loss via SCD1 downregulation. MITF directly activates Scd1 transcription, and the MITF–SCD1 axis mitigates SGN ferroptosis and hearing impairment in ototoxic ouabain and cisplatin models, revealing a lipid metabolic vulnerability and therapeutic target for sensorineural hearing loss.

(Molecular Therapy 31, 344–361; February 2023)

Li and colleagues identified RhoA as a “redox rheostat” governing mitochondrial dynamics during oncolytic virotherapy and thereby engineered rNDV-RHOA, an NDV-based oncolytic virus overexpressing RhoA. This tumor-targeted RhoA overexpression synergizes oxidative stress and viral oncolysis, transcending conventional oncolysis by surmounting tumor heterogeneity through exploiting inherent tumor redox dependency.

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.

This study characterizes a GalNAc-C5 small interfering RNA with potent in vitro and in vivo activity. Single subcutaneous dosing sustains long-term C5 suppression in cynomolgus monkeys with IgA nephropathy, outperforming Nefecon in blocking glomerular complement deposition, supporting its standalone or combinational clinical application.

Liu and colleagues develop a dendritic cell vaccine loaded with the gut commensals Bacteroides fragilis (DC-Bf), which triggers CD8+ T cell-dependent antitumor immune responses via MHC-I-mediated cross-presentation and interleukin-12 secretion, and enhances the efficacy of PD-1 antibody by improving the immunosuppressive tumor microenvironment and diversifying the T cell receptor repertoire.

Liu and colleagues developed a robust in cellulo plasmid DNA replication system in human cells for replicating plasmid-borne adeno-associated virus (AAV) Rep/Cap genes during recombinant AAV (rAAV) production. This new approach not only enables a 10- to 20-fold plasmid reduction to significantly lower manufacturing costs but also substantially enhances rAAV potency, titer, and purity.

This study developed a multi-layer inducible RNA switch that achieves transient expression of gene-delivery vectors in hepatic and non-hepatic tissues. As an exemplary application, this RNA switch triggers pulsive expression of gene editors that reduces the off-target effects and immunotoxicity of gene editing.

In the infection courses of different SARS-CoV-2 variants, disease outcomes and signatures were delineated by physiological changes, viral load, pathology, and pulmonary transcriptome analysis. This multi-dimensional landscape of disease outcomes and underlying mechanisms might provide important clues for immunotherapy of SARS-CoV-2 infection and pneumonia caused by other respiratory viruses.

MNK1 acts as a structural shield on MYH9, preventing YAP1-mediated platelet activation. Developing MD2 to lock this MNK1-MYH9 complex introduces a safe antithrombotic strategy, shifting the therapeutic paradigm from kinase inhibition to stabilizing protein-protein interactions against immunothrombosis.

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.

CAR T cells engineered to secrete tumor-localized anti-EpCAM bispecific T cell engagers (BTCEs) overcome antigen escape and heterogeneity across multiple epithelial carcinomas in preclinical models, achieving complete tumor eradication where conventional single-target CAR T cell therapies often failed, supporting broad translational potential for solid tumor immunotherapy.

Yang and colleagues demonstrate that lipid nanoparticle-mediated precise hepatic ASGR1 base editing safely produces robust and durable lipid lowering in an LDLR-deficient mouse model of familial hypercholesterolemia. Their work further benchmarks the lipid-lowering effects of ASGR1 and ANGPTL3 editing and supports combined ASGR1/ANGPTL3 targeting for enhanced cholesterol lowering.