Yang, Jin, and colleagues systematically evaluated three liver-targeted gene knock-in strategies—homology-directed repair (HDR), homology-independent targeted integration (HITI), and homology-mediated end joining (HMEJ)—in two mouse models of human genetic diseases. Their findings highlight the comprehensive advantages of the HMEJ approach and its strong potential for clinical translation.

Novel CAR-T cells with enhanced association rate constants and self-interaction of the receptor were developed by introducing arginine residues into the light-chain framework region-3 of scFv. These CAR-T cells demonstrated superior cell-killing efficacy, prolonged persistence in vivo. This arginine-cluster strategy improves CAR-T cell efficacy by modulating CAR properties.

Retinal delivery of an exon-specific U1 snRNA via AAV2 corrects ELP1 splicing, preserving retinal ganglion cell survival and function, leading to restoration of visual performance in a mouse model of familial dysautonomia. These findings establish ExSpeU1-based splicing modulation as a therapeutic strategy for FD-associated vision loss.

Björklund, Engel, and colleagues screened a barcoded AAV library in non-human primates to identify capsids capable of transducing entire neural networks. They report MNM004, a superior cross-species retrograde transporter, and MNM021, a unique variant with both robust local expression and efficient retrograde spread, offering new tools for treating CNS diseases.

NRF2 activation resolves neuropathic pain through dual antioxidant and NaV1.7-suppressive mechanisms. Insufficient NRF2 underlies pain chronicity, while its activation inhibits pathological sodium currents via NEDD4-2 in dorsal root ganglion neurons. The identified activators, echinacoside and artesunate, offer a promising therapeutic strategy by engaging these endogenous protective pathways.

In this work, Ha and collogues demonstrate clinical-scale manufacturing of a CRISPR gene-corrected regulatory T cell product for the treatment of IL2RA-deficiency resulting from compound heterozygous mutations in IL2RA and provide a framework for the treatment of other inborn errors of immunity.

Yu and colleagues identify circPTK2 as a fibroblast-specific circular RNA that is significantly upregulated in pulmonary fibrosis. By promoting fibroblast activation in an m6A methylation-dependent manner and sequestering miR-484/miR-125a-3p to boost YAP1/FYN mediated STAT3 signaling, circPTK2 offers a precise therapeutic target for pulmonary fibrosis.

One Sentence Summary: A gene therapy strategy for GBA1 related diseases, such as Gaucher Disease, GBA-PD with an engineered payload that robustly cross-corrects enhancing therapeutic footprint

BCMA CAR-T cells are effective in the treatment of Multiple Myeloma, but remissions are usually transient. Rehm and colleagues show that a sizable number of patients have BCMA-deficient and BAFF-R-expressing tumor cells. CAR-T cells equipped with a dual anti-BAFF-R/anti-BCMA CAR result in improved tumor eradication and may prevent immune escape.

Stergiopoulos and colleagues demonstrate that the FDA-approved SSRI paroxetine combined with oncolytic measles virus-based immunovirotherapy enhances T-cell mobilization and activation by increasing S1P1 expression on bone marrow lymphocytes, improving survival in a syngeneic GBM mouse model. This highlights paroxetine’s translational potential to decrease immunosuppression and enhance immunotherapy/immunovirotherapy efficacy in GBM.

MiR-138 inhibition potentiates oncolytic activities of G47Δ by enhancing viral replication and tumor cell killing via regulating the viral protein ICP0, and by augmenting antitumor immunity via STAT1-mediated pathways. The microRNA–targeted combination is a rational therapeutic strategy for improving the efficacy of oncolytic virus therapy for malignant brain tumors.

Berezovski and colleagues developed three DNA aptamers with high affinity for the receptor-binding domain of the SARS-CoV-2 S1 protein. Their integration into a proximity ligation assay enabled picomolar detection of the spike protein, demonstrating a highly sensitive and specific nucleic acid–based platform for viral diagnostics.

Abdollahi and colleagues show that decreasing levels of a long noncoding-RNA, lncMGC, by genetic knockout or GapmeR antisense oligonucleotides can attenuate obesity, obesity induced adipose tissue dysfunction, and insulin resistance in mice. Targeting lncMGC may represent a promising therapeutic strategy for treating adipose dysfunction, obesity, and associated complications.

2′MOE-AO dose-dependently inhibits DUX4, and the dosage correlates to muscle uptake in FLExDUX4 mice. Long term subcutaneous administration significantly reduced DUX4 in several muscles of forelimb and hindlimb, reduced muscle pathology, and improved muscle function in FLExDUX4 and ACTA1-MCM;FLExDUX4 FSHD mice.

This study assessed the potential of using RNA-targeting CRISPR system and engineered U1 to modulate ABCA4 splicing.

Tamadon and colleagues present a systematic review and meta-analysis of in vitro studies evaluating mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in breast cancer. Their findings reveal that MSC-EVs significantly reduce tumor cell viability and migration while enhancing apoptosis, highlighting both therapeutic promise and potential dormancy-associated risks for translational applications.

Targeting two distinct antigens via bi- or trispecific T cell engagers encoded by oncolytic Adenoviruses is explored to address the problem of tumor heterogeneity. Different antibody formats and expression strategies are investigated in vitro, establishing a promising platform for next-generation, dual-targeted viro-immunotherapy.

Advanced cancer embodies the principle of relentless adaptation, reminding us that molecular therapy cannot be developed apart from the biological complexity that underlies lethality. Castration-resistant prostate cancer (CRPC) exemplifies this challenge: persistent androgen receptor (AR) signaling fuels tumor growth despite androgen-deprivation therapy, leading to inevitable resistance to second-generation AR inhibitors.1 Mechanisms converge on AR reactivation through the overexpression of full-length AR, ligand-binding domain mutations, or constitutively active splice variants such as AR-V7, which escape inhibition and correlate with poor prognosis.

MicroRNAs (miRNAs) are key regulators of gene expression, which play central roles in cell differentiation, tissue homeostasis, and disease pathogenesis.1,2,3 This functional significance has motivated the exploration of miRNAs as novel therapeutic agents and targets.4,5 A critical step in developing such therapies is to identify essential functional miRNAs.6 However, the high costs and ethical constraints of experimental validation have resulted in a critical scarcity of essentiality labels for human miRNAs, directly limiting the development of reliable computational predictors.

Innate immune cell-derived BAFF promotes the generation of pathogenic ICOSL+ B cells via non-canonical NF-κB signaling, linking innate and adaptive immunity in type 1 diabetes. Targeting the BAFF–ICOSL axis restrains inflammatory B-T cell responses and alleviates autoimmune progression, revealing a potential therapeutic strategy for T1D.

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

A humanized low-affinty Nectin-4 targeting CAR that exhibited strong antitumor activity and reduced sensitivity to low antigen levels was found to cause on-target/off- tumor toxicities in a first-in-human study, affecting skin, oromucosal, and gastrointestinal tissues.

Tan and colleagues demonstrated that the LPP-HNH mRNA vaccine, which sequentially encodes H1 stem, N1 NA, and H3 stem proteins connected with a 2A peptide, elicits comprehensive immune responses and offers cross-protection against influenza A viruses H1N1, H3N2, and H5N1, and provides a promising strategy for developing broad-spectrum influenza vaccines.

Way and colleagues explore strategies to enhance the efficacy of a recombinant oncolytic vaccinia virus designed for greater tumour specificity in ovarian cancer therapy. Their findings reveal that combining this virus with vinorelbine significantly improves survival in a syngeneic model of high grade serous ovarian carcinoma