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Catalytically inactive CRISPR‐Cas13 (dCas13)‐based base editors can achieve the conversion of adenine‐to‐inosine (A‐to‐I) or cytidine‐to‐uridine (C‐to‐U) at the RNA level, however, the large size of dCas13 protein limits its in vivo applications. Here, a compact and efficient RNA base editor (ceRBE) is reported with high in vivo editing efficiency. The larger dCas13 protein is replaced with a 199‐amino acid EcCas6e protein, derived from the Class 1 CRISPR family involved in pre‐crRNA processing, and conducted optimization for toxicity and editing efficiency. The ceRBE efficiently achieves both A‐to‐I and C‐to‐U base editing with low transcriptome off‐target in HEK293T cells. The efficient repair of the DMD Q1392X mutation (68.3±10.1%) is also demonstrated in a humanized mouse model of Duchenne muscular dystrophy (DMD) after AAV delivery, achieving restoration of expression for gene products. The study supports that the compact and efficient ceRBE has great potential for treating genetic diseases. [ABSTRACT FROM AUTHOR]

• By inhibiting SLC7A11/xCT with the inhibitor sulfasalazine and nanoreactors with tetrasulfide bond (-s-s-s-s-)- as the backbone, tumor cell glutathione synthesis is suppressed and its consumption is promoted. • Decreased glutathione content inhibits GPX4 synthesis, promotes intracellular lipid peroxide accumulation, and induces ferroptosis in tumor cells. • The photosensitizer DVDMS produces ROS under ultrasound, which, together with Fe3+, promotes lipid peroxide generation. • Targeted delivery of USP39 shRNA can efficiently silence USP39 gene expression under ultrasound stimulation, inhibiting cell proliferation and selectively inducing autophagy-dependent ferroptosis. The promotion of cellular ferroptosis through ultrasound (US)-assisted Fenton chemistry has emerged as a promising strategy for tumor therapy. To enhance the therapeutic effect, we designed a GSH-responsive ultrasound-driven nanoreactor for RNA interference (RNAi)-intensified ferroptosis in synergistic sono-chemodynamic therapy. Our nanoreactor comprises Fe3+/tetrasulfide bond (-s-s-s-s-) enriched dendritic organosilica encapsulating USP39 shRNA, along with co-loading of sinophoryrin sodium (DVDMS) and sulfasalazine (SAS). Hyaluronic acid surface functionalization ensures high tumor accumulation for active targeting of tumor cells. Upon internalization into tumor cells, the nanoreactor degrades upon the triggering of intracellular overproduced GSH. Ultrasound-triggered release of DVDMS generates large amounts of ROS, synergizing with Fe-catalyzed Fenton chemistry. The simultaneous depletion of glutathione peroxidase 4 and GSH by SAS and Fe3+ weakens the ROS-scavenging system, leading to tumoral redox dyshomeostasis via oxidative stress amplification. This results in the accumulation of lipid peroxide in tumor cells, efficiently inducing ferroptosis. Additionally, USP39 shRNA effectively silences the expression of the USP39 gene in cells, inhibiting tumor cell proliferation, while promoting ATG5 gene expression to intensify ferroptosis. Our work provides a promising nanoreactor for high-efficiency synergistic tumor therapy via RNAi-intensified ferroptosis, highlighting the potential of sono-chemodynamic therapy in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Luminal subtype breast cancer accounts for a predominant number of breast cancers. Considering the heterogeneity of the disease, it is urgent to develop novel biomarkers to improve risk stratification and optimize therapy choices. Long non-coding RNA (lncRNA) represents an emerging and understudied class of transcripts that play a significant role in cancer biology. Growing knowledge of cancer-associated lncRNAs contributes to the development of molecular markers for prognosis evaluation and gene therapy. Materials and methods: Three pairs of primary luminal subtype breast cancer tissues and adjacent non-cancerous tissues were collected and sequenced. EBseq algorithm was used to identify differentially expressed lncRNAs. RNA sequencing data from The Cancer Genome Atlas (TCGA) database were used to validate the robustness of our RNA-seq results. Kaplan-Meier and Cox regression analyses were utilized to assess the association between the lncRNAs and overall survival of patients in TCGA cohort. Results: A total of 796 lncRNAs were significantly dysregulated in luminal subtype breast cancer, including 436 upregulated and 360 downregulated lncRNAs. Among them, FAM83H antisense RNA 1 (FAM83H-AS1) was the most upregulated lncRNA, whereas GSN antisense RNA 1 (GSN-AS1) was the most downregulated lncRNA. Moreover, we proved that the high expression level of FAM83H-AS1 indicated unfavorable prognosis not only in luminal subtype breast cancer but also in all subtype breast cancers. To the best of our knowledge, this is the first report indicating that FAM83H-AS1 was involved in luminal subtype breast cancer and was an independent prognostic indicator. Conclusion: Our study provides a rich resource to the research community for further identifying lncRNAs with diagnostic and therapeutic potentials and exploring biological function of lncRNAs in luminal subtype breast cancer. [ABSTRACT FROM AUTHOR]