Herein, we present a novel method to specifically increase a messenger RNA's (mRNA) expression at the post-transcriptional level. This is accomplished using what we term a "Tethered mRNA Amplifier." The Tethered mRNA Amplifier specifically binds an mRNA's 3' untranslated region and enhances its stability/translation, often doubling protein output. We test this approach on several transcripts associated with haploinsufficiency disorders and increase their steady-state expression in cell culture. We suggest this approach may be a tenable therapeutic modality with precise activity and broad-spectrum application.
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http://dx.doi.org/10.1002/biot.202200214 | DOI Listing |
Biomaterials
January 2025
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, 518107, China; School of Medicine, Hangzhou City University, Hangzhou, 310015, China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315040, China. Electronic address:
T cell therapy for solid tumors faces significant challenges due to the immune off-target attack caused by the loss of tumor surface antigens and inactivation in acidic tumor microenvironment (TME). Herein, we developed a bifunctional immunomodulator (MO@NAL) by loading ovalbumin (OVA; model antigen) mRNA (mOVA) onto lysozyme-coated layered double hydroxide nano-aluminum adjuvant (NA). The NA's inherent alkalinity effectively neutralizes the excess acid within the TME and suppresses regulatory T cells, creating a favorable microenvironment to enhance cytotoxic T cell infiltration and activation in tumors.
View Article and Find Full Text PDFbioRxiv
December 2024
Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA.
Lipid nanoparticles (LNP) are the most clinically advanced non-viral gene delivery system. While progress has been made for enhancing delivery, cell specific targeting remains a challenge. Targeting moieties such as antibodies can be chemically-conjugated to LNPs however, this approach is complex and has challenges for scaling up.
View Article and Find Full Text PDFCell Rep
December 2024
Department of Breast Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. China. Electronic address:
Aberrant N-methyladenosine (mA) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of mA modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated mA modification on 28S rRNA are upregulated in various cancers and correlated with poor survival. Functionally, ZCCHC4 promotes intrahepatic cholangiocarcinoma (ICC) progression via its catalytic activity.
View Article and Find Full Text PDFmSphere
December 2024
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Unlabelled: The eukaryotic CCR4-NOT deadenylase complex is a highly conserved regulator of mRNA metabolism that influences the expression of the complete transcriptome, representing a prime target for a generalist bacterial pathogen. We show that a translocated bacterial effector protein, PieF (Lpg1972) of , directly interacts with the CNOT7/8 nuclease module of CCR4-NOT, with a dissociation constant in the low nanomolar range. PieF is a robust inhibitor of the DEDD-type nuclease, CNOT7, acting in a stoichiometric, dose-dependent manner.
View Article and Find Full Text PDFCancers (Basel)
November 2024
Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
The lens epithelium derived growth factor of 75 kD (LEDGF/p75) is a transcription co-activator and epigenetic reader that has emerged as a stress oncoprotein in multiple human cancers. Growing evidence indicates that it promotes tumor cell survival against certain therapeutic drugs. The amino (N)-terminal region of LEDGF/p75 contains a PWWP domain that reads methylated histone marks, critical for recognizing transcriptionally active chromatin sites.
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