Bispecific antibodies pairing a shared 4-1BB epitope with non-overlapping HER2 epitopes drove HER2-dependent 4-1BB clustering, amplifying T-cell activation and tumor growth inhibition. In vivo, this pairing enhanced antitumor efficacy and tumor infiltration, while reducing systemic inflammation compared to urelumab - establishing a generalizable strategy for TNFRSF-targeted immunotherapy.

Shim and colleagues develop DLMEH, a metabolically stabilized D-leucine prodrug that bypasses first-pass catabolism. DLMEH activates Sestrin2-dependent mTORC1 signaling, restoring muscle protein synthesis in dexamethasone-induced atrophy. In rat models, DLMEH preserves muscle mass, strength, and endurance superior to L-leucine, supporting DLMEH as a first-in-class candidate for sarcopenia.

Koo and colleagues demonstrate that Un1Cas12f1 recognizes an expanded PAMs, and enables multiplexed genome editing from a single CRISPR array. Delivered as an all-in-one AAV, this compact Un1Cas12f1 system excises Dmd exon 23 in vivo, restores the reading frame and dystrophin expression in a mouse model of Duchenne muscular dystrophy.

Pathogenic variants in the gene encoding 6-pyruvoyl-tetrahydropterin synthase cause primary BH4 deficiency (PBD), leading to hyperphenylalaninemia and reduced monoamine neurotransmitter synthesis. This phase 1/2 study in eight patients with PBD found that sepiapterin increased blood BH4 and rapidly normalized blood phenylalanine levels, with no dose-limiting toxicity or dose-related adverse events.

The recent FDA approval of OTOF gene therapy is a major milestone for the field of hearing loss.1 However, auditory gene therapy still lags behind other fields in terms of clinical trials and approvals. A myriad of promising preclinical studies have been published for pediatric and juvenile-onset hearing loss, but far fewer have demonstrated similar promise for adult-onset hearing disorders. One thing is clear: effective gene delivery to adult hair cells and spiral ganglion neurons remains a key challenge for translating gene therapies for sensorineural hearing loss.

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

Oncolytic herpes simplex virus 1 (oHSV) is a promising viro-immunotherapy that directly lyses tumor cells while reshaping the tumor microenvironment (TME) and stimulates anti-tumor immunity. However, despite encouraging preclinical and clinical activity, treatment-induced adaptations in tumor cells and the surrounding microenvironment can promote survival, repair, repopulation, immune escape, and recurrence, thereby limiting durable therapeutic benefit. In our recent article published in Cell Death & Disease,1 we asked why oHSV often fails to achieve durable tumor control and whether the adaptive resistance it induces can be therapeutically overcome.

Protein therapies have been developed to bind numerous disease-associated targets but can cause off-site toxicities when healthy tissues also express their target. Therefore, emergent strategies have designed masked, conditionally activated protein therapies. This review focuses on the design and effectiveness of protein-based masks for cytokines, antibodies, and their derivatives.

Yuzaki and colleagues identify biallelic CBLN1 variants as a cause of early-onset hereditary ataxia and show that loss of extracellular CBLN1 disrupts cerebellar synapses. Astrocyte-targeted AAV delivery restores synaptic CBLN1 and rescues circuit and motor dysfunction, establishing extracellular synaptic organizer replacement as a therapeutic strategy.

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.

Lu and colleagues identify BRD4 as a central epigenetic driver of vesicant-induced corneal injury. Using reproducible mouse and rabbit models, they show that short-term topical BRD4 inhibition suppresses acute inflammation and provides durable protection of corneal clarity, stromal organization, endothelial integrity, and neovascularization, supporting translational therapy for chemical eye injuries.

The authors develop AminiCRoff, a compact dAsCas12f1-based epigenetic silencer compatible with single-AAV delivery. AminiCRoff mediates durable, heritable gene silencing comparable to the larger CRISPRoff and represses endogenous MYC to inhibit tumor cell proliferation, providing a versatile platform for in vivo epigenome editing.

Glaucoma is a leading cause of blindness worldwide.1 Although it is traditionally managed as a pressure-related disease, retinal ganglion cell (RGC) degeneration can continue despite substantial reductions in intraocular pressure. This has intensified interest in the intrinsic mechanisms that determine RGC vulnerability and resilience. Among these, mitochondrial dysfunction and metabolic insufficiency have emerged as particularly compelling therapeutic targets. RGCs have exceptional energetic requirements imposed by maintenance of long axons, action-potential propagation, axonal transport, and synaptic activity.

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.

Structure-guided design combined with protein language model-guided engineering and sgRNA optimization enables the development of a compact and highly efficient CRISPR–Cas12f genome editor. This integrated strategy substantially improves genome-editing activity while preserving high specificity, expanding the therapeutic potential of compact CRISPR systems.

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.