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| Open AccessLipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
There is a need for development of efficient delivery vehicles for the treatment of inherited retinal degeneration with gene therapy. Here, Gautam et al., show that surface modifications of lipid nanoparticles with PEG variants alters their cellular tropism allowing gene editing in diverse retinal cell types in mice.
- Milan Gautam
- , Antony Jozic
- & Gaurav Sahay
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Article
| Open AccessA renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury
KIM1 is dramatically upregulated in acute kidney injury (AKI) and but how KIM1 affects AKI remains unknown. Here, the authors report that renal specific Kim1 knockout relieves AKI, unveil a YY1-KIM1-DR5 axis in the progression of AKI, and suggest potential therapeutic strategies against AKI.
- Chen Yang
- , Huidie Xu
- & Ling Zheng
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Article
| Open AccessMultivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2
There are currently two types of antiviral drugs – neutralizing antibodies and small molecule inhibitors. Here, the authors report the development of bicyclic peptides that combine the advantages of both and show their antiviral capacity against SARS-CoV-2 in vitro as well as in small animal models.
- Katherine U. Gaynor
- , Marina Vaysburd
- & Leo C. James
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Article
| Open AccessStructural mapping of Nav1.7 antagonists
Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.
- Qiurong Wu
- , Jian Huang
- & Nieng Yan
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Article
| Open AccessSmart thrombosis inhibitors without bleeding side effects via charge tunable ligand design
Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.
- Chanel C. La
- , Stephanie A. Smith
- & Jayachandran N. Kizhakkedathu
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Article
| Open AccessTrio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open AccessBreaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application
Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.
- Alban Guesdon-Vennerie
- , Patrick Couvreur
- & Guillaume Bort
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| Open AccessEfficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid)
Encapsulation of bioactive peptides in slow-release particles is complex and relies on organic solvents. Here, the authors absorb peptides in a polymer phase from water, creating a simple low-cost encapsulation process in a class of polymer depot.
- Morgan B. Giles
- , Justin K. Y. Hong
- & Steven P. Schwendeman
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Article
| Open AccessPeptide nano-blanket impedes fibroblasts activation and subsequent formation of pre-metastatic niche
Primary tumors “spread the spark” by establishing a pre-metastatic niche. Here the authors develop an in-situ assembled peptide FR17 to serve as a “flame-retarding blanket” to extinguish the “fire” of the pre-metastatic microenvironment.
- Yi Zhou
- , Peng Ke
- & Jianqing Gao
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Article
| Open AccessVariant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models
C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.
- Yuanjing Liu
- , Jean-Cosme Dodart
- & Robert H. Brown Jr.
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Article
| Open AccessDiscovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.
- Edmund C. Lee
- , Tania Valencia
- & Vishal Patel
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Article
| Open AccessPolymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity
There is interest in developing long-lasting local anaesthetics for a range of applications. Here, the authors report on the application of tetrodotoxin conjugated to amphiphilic biodegradable polymer to reduce systemic toxicity, achieve sustained release and investigate application as a local anaesthetic.
- Chao Zhao
- , Andong Liu
- & Daniel S. Kohane
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Article
| Open AccessA toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages
Turning tumour promoting macrophages into an anti-tumour phenotype is an attractive therapeutic strategy. Here, the authors develop a polysaccharide-based structure that mimicks pathogen-associated molecular patterns and, by activating the toll-like receptors on macrophage surface, promotes a safe anti-tumour immune response in mouse models.
- Yanxian Feng
- , Ruoyu Mu
- & Chunming Wang
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Article
| Open AccessAntidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Mitochondrial uncoupling is a treatment strategy for metabolic diseases that reduces the efficiency of mitochondrial oxidative phosphorylation and ATP generation. Here the authors characterize the pharmacokinetic and therapeutic properties of the liver-localized mitochondrial uncoupler OPC-163493, which leads to amelioration of diabetes and hypertension in several rodent disease models.
- Naohide Kanemoto
- , Takashi Okamoto
- & Seiji Sato
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Article
| Open AccessTamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy
X-linked myotubular myopathy (XLMTM) is a severe muscle disease with no effective treatment. Here, the authors show that tamoxifen, a drug used to treat breast cancer, rescues the pathology in a mouse model of the disease, at least in part by normalizing expression of the disease modifier proteins DNM2 and BIN1
- Elinam Gayi
- , Laurence A. Neff
- & Leonardo Scapozza
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Article
| Open AccessCell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes
Therapeutic alteration of protein expression using modified mRNA is limited by immunogenicity and instability in vivo. Here the authors use antibody-coated lipid nanoparticles to deliver mRNA to leukocytes and drive expression of anti-inflammatory cytokines in an inflammatory bowel disease mouse model.
- Nuphar Veiga
- , Meir Goldsmith
- & Dan Peer
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Article
| Open AccessMechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics
Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.
- Nicolas Bertrand
- , Philippe Grenier
- & Omid C. Farokhzad
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Article
| Open AccessBiosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents
Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.
- Junying Ma
- , Hongbo Huang
- & Jianhua Ju
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| Open AccessNon-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis
Fibroblast Growth Factor 19 (FGF19) neutralizing antibodies inhibit hepatocellular carcinoma (HCC) growth but have safety issues. Here, the authors show that FGF19 promotes HCC by activating STAT3 signalling via IL-6 production and that targeting IL-6 pathway abolishes FGF19-induced HCC without side effects.
- Mei Zhou
- , Hong Yang
- & Lei Ling
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| Open AccessSynthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care
Current biopharmaceutical manufacturing platforms use single biologic-producing cell lines cultured at large scales. Here the authors develop a small-scale, portable biomanufacturing platform to produce single dose IFNa2b and rHGH from a single engineered strain of P. pastoris.
- Pablo Perez-Pinera
- , Ningren Han
- & Timothy K. Lu