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Article
| Open Access
Single-cell quantification and dose-response of cytosolic siRNA delivery
Endosomal escape and subsequent cytosolic delivery of siRNA therapeutics is inefficient, and quantification is difficult. Here the authors report a confocal microscopy-based method to quantify cytosolic delivery of fluorescently labelled siRNA during lipid-mediated delivery.
- Hampus Hedlund
- , Hampus Du Rietz
- & Anders Wittrup
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Article
| Open Access
Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models
Chemically modified siRNAs distinguish between mutant and normal huntingtin based on a single nucleotide difference and lower mutant huntingtin specifically in patient derived cells and in a mouse model of Huntington’s disease.
- Faith Conroy
- , Rachael Miller
- & Edith L. Pfister
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Article
| Open Access
GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
GAPDH is generally considered a housekeeping gene and functions in glycolysis. Here, the authors show that GAPDH has a role in promoting vesicle clustering in endosomes and can load siRNA onto the surface of extracellular vesicles, which can be exploited therapeutically.
- Ghulam Hassan Dar
- , Cláudia C. Mendes
- & Matthew J. A. Wood
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Article
| Open Access
Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance
Cas13b can be harnessed to target and degrade RNA transcripts inside a cellular environment. Here the authors reprogram Cas13b to target SARSCoV-2 transcripts in infected mammalian cells and reveal its resilience to variants thanks to single mismatch tolerance.
- Mohamed Fareh
- , Wei Zhao
- & Joseph A. Trapani
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Article
| Open Access
Programmably tiling rigidified DNA brick on gold nanoparticle as multi-functional shell for cancer-targeted delivery of siRNAs
Small interfering RNA (siRNA) is used to regulate gene expression for therapeutic purposes, but the design of stable and efficient siRNA delivery systems is challenging. Here, the authors develop a siRNA-encapsulated and aptamer-incorporated core/shell nanoparticle for controlled siRNA delivery, with high stability, tumor-specific targeting and long circulation time.
- Chang Xue
- , Shuyao Hu
- & Zai-Sheng Wu
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Article
| Open Access
Imaging small molecule-induced endosomal escape of siRNA
Therapeutic siRNA becomes trapped in endosomes, limiting its efficacy. Here the authors use fluorescently-tagged galectin-9 as a biosensor for membrane damage to monitor endosomal escape of cholesterol-conjugated siRNA following treatment of small molecule membrane-destabilising drugs.
- Hampus Du Rietz
- , Hampus Hedlund
- & Anders Wittrup
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Article
| Open Access
A RNA producing DNA hydrogel as a platform for a high performance RNA interference system
Interfering RNA have a range of therapeutic and research based applications, issues with delivery have made systems that make siRNA in situ of interest. Here, the author report on the creation of a DNA hydrogel with improved stability and transcription efficiency over plasmid DNA.
- Jaejung Song
- , Minhyuk Lee
- & Nokyoung Park
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Article
| Open Access
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity
A subset of chemically-modified siRNAs conjugated to trivalent GalNAc may fail during nonclinical development due to rat hepatotoxicity. Here, the authors show that hepatotoxicity may be accounted for by microRNA-like off-target effects of siRNA and can be mitigated by a thermally destabilizing modification in the siRNA seed region.
- Maja M. Janas
- , Mark K. Schlegel
- & Vasant Jadhav
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Article
| Open Access
Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis
Chitinase-3-like-1 (Chi3l1) has been involved in inflammation and pulmonary metastasis. Here the authors show that Chi3l1 inhibits the T cell response by negatively regulating their activation and that, in a mouse model of melanoma, T cell-targeted silencing of Chi3l1 results in reduced lung metastasis.
- Do-Hyun Kim
- , Hong-Jai Park
- & Je-Min Choi
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Article
| Open Access
Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer
Treatment of pancreatic ductal adenocarcinoma is still challenging and patients survival has only marginally improved in the last decade. Here the authors produce a PGA-based polymeric nanocarrier for the dual delivery of miR-34a-mimic and PLK1-targeting siRNA resulting in killing of pancreatic cancer cells in vivo.
- Hadas Gibori
- , Shay Eliyahu
- & Ronit Satchi-Fainaro
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Article
| Open Access
PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery
The anti-diabetic drug Metformin also possesses anti-tumour activity. Here, the authors synthesize polymeric Metformin-based nanoparticles that still exert intrinsic biological activity through AMPK and mTOR regulation and can systematically deliver VEGF siRNA, significantly reducing lung cancer growth in mice.
- Yi Zhao
- , Wei Wang
- & Leaf Huang
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Article
| Open Access
Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
Therapeutic oligonucleotides can be made more stable by substituting their achiral phosphodiester groups for chiral phosphorothioate linkages. Here, the authors present a synthesis of phosphorothioated RNAs, where the activator controls strand stereochemistry, and also the activity of assembled siRNAs.
- Hartmut Jahns
- , Martina Roos
- & Jonathan Hall
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Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity
Robust and reliable structure–function relationships are valuable for the development of potent drug delivery systems. Here, the authors use a library of lipid-like materials to predict in vivosiRNA delivery efficacy without any biological testing.
- Kathryn A. Whitehead
- , J. Robert Dorkin
- & Daniel G. Anderson
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Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice
Integrin proteins regulate important cellular processes such as proliferation and differentiation. Here the authors show that siRNA-mediated knockdown of two integrin subunits slows down progression of hepatocellular carcinoma in mice by reducing activation of the METoncogene.
- Roman L. Bogorad
- , Hao Yin
- & Victor Koteliansky
Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin