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| Open AccessNon-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and viral vaccines
Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy.
- Wenjun Zhu
- , Ting Wei
- & Zhuang Liu
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Article
| Open AccessAnti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Poor renal distribution of antibody-based drugs limits the treatment efficiency for diabetic nephropathy and causes side effects. Here, the authors prepare an antibody fragment drug conjugate, antiVEGFR2 F(ab′)2-SS31, improving renal distribution and meriting drug validation in diabetic nephropathy therapy.
- Di Liu
- , Yanling Song
- & Yongzhong Du
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Article
| Open AccessAn IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants
In this study, the authors report the development of an inhalable IgM-like ACE2 and show that it broadly neutralizes SARS-CoV-2 variants, lowers viral loads and lung pathology in hamsters when administered early, and has good safety profiles in rats and monkeys.
- Juan Liu
- , Fengfeng Mao
- & Wenhui Li
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Article
| Open AccessTreatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo
Liposome-mediated gene editing was used to abolish a mutation in gene Atp2b2 and recover hearing in a mouse model of dominant deafness. Editing was also used to target two mutations to recover hearing. The study detected large deletions due to editing.
- Yong Tao
- , Veronica Lamas
- & Zheng-Yi Chen
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Article
| Open AccessIdentification of scaffold proteins for improved endogenous engineering of extracellular vesicles
Extracellular vesicles are naturally occurring nanoparticles that are gaining ground as delivery modalities for therapeutics. Here, the authors conducted a large-scale screening programme to identify potential scaffold proteins for cargo loading into extracellular vesicles.
- Wenyi Zheng
- , Julia Rädler
- & Samir EL Andaloussi
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Article
| Open AccessBioinspired engineering of fusogen and targeting moiety equipped nanovesicles
Active targeting and cytosolic delivery of therapeutic payloads are challenging in small extracellular vesicle-based drug delivery systems. Here, the authors engineer fusogen and targeting moiety co-functionalized cell-derived nanovesicles, which can selectively bind to target cells and efficiently fulfill cytosolic delivery through membrane fusion.
- Lixue Wang
- , Guosheng Wang
- & Yuan Wan
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Article
| Open AccessTargeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct
Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.
- Alexandra Gehrlein
- , Vinod Udayar
- & Ravi Jagasia
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Article
| Open AccessImproved pharmacodynamics of epidermal growth factor via microneedles-based self-powered transcutaneous electrical stimulation
The use of epidermal growth factor for wound healing is limited by transdermal permeability, reduction, and receptor desensitization. Here the authors develop a microneedle-based self-powered transcutaneous electrical stimulation system to overcome these challenges.
- Yuan Yang
- , Ruizeng Luo
- & Zhong Lin Wang
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Article
| Open AccessFormation of synthetic RNA protein granules using engineered phage-coat-protein -RNA complexes
Condensates composed of RNA and proteins are biologically vital but generally poorly understood. Here, the authors engineer synthetic RNA-protein condensates and show that gel-like condensates form as a result of liquid-gel phase separation in a specific and selective fashion.
- Naor Granik
- , Noa Katz
- & Roee Amit
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Article
| Open AccessLigand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy
Displaying the correct surface functionality at the right time is important for efficient drug delivery. Here, the authors report on the pH-responsive, sequential presentation of cell-penetrating peptide and liver-targeting moiety designed to improve intestinal absorption and liver targeting and demonstrate this with insulin delivery in vivo.
- Tiantian Yang
- , Aohua Wang
- & Yong Gan
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Article
| Open AccessSpatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy
Several approaches have been recently proposed to engineer bacteria for cancer immunotherapy. Here the authors design an ultrasound-responsive bacterium for the controlled release of IFNy at the tumor site, promoting anti-tumor immune responses in preclinical models.
- Yuhao Chen
- , Meng Du
- & Fei Yan
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Article
| Open AccessRegulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage
Secreted proteins, such as hormones or cytokines, are key mediators in multicellular organisms. Here the authors present two genetically encoded orthogonal regulatory secretion systems that enables inducible protein release and construction of logic gates.
- Arne Praznik
- , Tina Fink
- & Roman Jerala
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Article
| Open AccessBone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction
Here the authors show that a monoclonal antibody against a soluble isoform of Bone Morphogenetic Protein 1 prevents cardiac cell death, reducing fibrosis and preserving cardiac function after myocardial ischemia.
- Slobodan Vukicevic
- , Andrea Colliva
- & Serena Zacchigna
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Article
| Open AccessImplantable optical fibers for immunotherapeutics delivery and tumor impedance measurement
Immune checkpoint blockade antibodies have promising clinical applications, but suffer from severe toxicities and moderate response rates. Here the authors present an electrode-embedded, implantable optical fiber device with both local delivery and tumor impedance measurement capabilities to safely elicit durable anti-tumor immunity.
- Ai Lin Chin
- , Shan Jiang
- & Rong Tong
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Article
| Open AccessEfficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo
Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo.
- Siyuan Yu
- , Han Yang
- & Ningshao Xia
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Article
| Open AccessUnravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay
Our understanding of cytosolic delivery is hindered by existing methods for quantification which suffer from being indirect and showing low sensitivity. Here the authors report a SLEEQ (Split Luciferase Endosomal Escape Quantification) assay to assess cytosolic delivery of cell-penetrating peptides.
- Serena L. Y. Teo
- , Joshua J. Rennick
- & Colin W. Pouton
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Article
| Open AccessAn anionic human protein mediates cationic liposome delivery of genome editing proteins into mammalian cells
Inefficient delivery of proteins into mammalian cells limits their use in research and therapy. Here, the authors discover that ProTα, a small, intrinsically disordered human protein can facilitate efficient cationic lipid-mediated protein delivery of genome editing proteins into mammalian cells.
- Y. Bill Kim
- , Kevin T. Zhao
- & David R. Liu
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Article
| Open AccessThe glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells
Lysosomal replacement enzymes are taken up by cell surface receptors that recognize glycans, the effects of different glycan features are unknown. Here the authors present a gene engineering screen in CHO cells that allows custom N-glycan-decorated enzymes with improved circulation time and organ distribution.
- Weihua Tian
- , Zilu Ye
- & Zhang Yang
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Article
| Open AccessGenome editing in primary cells and in vivo using viral-derived Nanoblades loaded with Cas9-sgRNA ribonucleoproteins
A current challenge in genome editing is delivering Cas9 and sgRNA into target cells. Here the authors engineer a delivery system based on murine leukemia virus-like particles loaded with Cas9-sgRNA ribonucleoproteins to induce efficient genome editing in both cell culture and in vivo in mouse.
- Philippe E. Mangeot
- , Valérie Risson
- & Emiliano P. Ricci
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| Open AccessExtension of the crRNA enhances Cpf1 gene editing in vitro and in vivo
Optimization of the recently discovered Class 2 CRISPR protein Cpf1 has the potential to promote its applications in gene editing and therapeutics. Here, the authors find that extending the 5′ end of the crRNA can increase both the editing efficiency and delivery of Cpf1 in vitro and in vivo.
- Hyo Min Park
- , Hui Liu
- & Kunwoo Lee
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Article
| Open AccessThe fluorination effect of fluoroamphiphiles in cytosolic protein delivery
Proteins can serve as means of medical treatment, but their efficient delivery to cells is difficult. Here, the authors present a type of polymers, fluoroamphiphiles, acting as chemical chaperones that can facilitate the import of proteins into the inner compartment, i.e. cytosol, of cells.
- Zhenjing Zhang
- , Wanwan Shen
- & Yiyun Cheng
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Article
| Open AccessARMMs as a versatile platform for intracellular delivery of macromolecules
One of the challenges of biologic drug therapy is delivery into target cells and tissues. Here the authors present ARMMs (arrestin domain containing protein 1 mediated microvesicles) as a versatile platform for packaging and delivery of a myriad of molecules, including p53, RNAs and CRISPR-Cas9.
- Qiyu Wang
- , Jiujiu Yu
- & Quan Lu
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Article
| Open AccessDouble-layered protein nanoparticles induce broad protection against divergent influenza A viruses
Relatively well conserved domains of influenza A virus (IAV) proteins are potential candidates for the development of a universal IAV vaccine. Here, Deng et al. combine two such conserved antigens (M2e and HA stalk) in a double-layered protein nanoparticle and show that it protects against divergent IAVs in mice.
- Lei Deng
- , Teena Mohan
- & Bao-Zhong Wang
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Article
| Open AccessImproving the DNA specificity and applicability of base editing through protein engineering and protein delivery
Third-generation base editors consist of a catalytically disabled Cas9 fused to a cytidine deaminase and a base excision repair inhibitor, enabling efficient, precise editing of individual base pairs in DNA. Here the authors describe engineering and protein delivery of base editors to improve their DNA specificity and enable specific base editing in live animals.
- Holly A. Rees
- , Alexis C. Komor
- & David R. Liu
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Article
| Open AccessEngineered clearing agents for the selective depletion of antigen-specific antibodies
The depletion of antigen-specific, deleterious antibodies during therapy and diagnosis remains an unsolved challenge. Here the authors develop ‘Seldegs’, antigens linked to human Fc fragments with high affinity for the neonatal Fc receptor FcRn, to deplete MOG- and HER2-specific antibodies in mice.
- Siva Charan Devanaboyina
- , Priyanka Khare
- & E. Sally Ward
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Article
| Open AccessControl of type III protein secretion using a minimal genetic system
The type III secretion system is a needle-like molecular machine under tight regulatory control. Here the authors construct a synthetic type III secretion system gene cluster by deconstructing and rebuilding the wild-typeSalmonellapathogenicity island 1.
- Miryoung Song
- , David J. Sukovich
- & Christopher A. Voigt
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Article
| Open AccessExosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module
Exosomes have been identified as promising vehicles for the in vivodelivery of therapeutic molecules. Here the authors design a system to load protein cargos into exosomes during their biogenesis using optogenetic control of protein-protein interactions between the cargo and an exosome-localized partner.
- Nambin Yim
- , Seung-Wook Ryu
- & Chulhee Choi
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Article
| Open AccessdNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis
Most of the cell penetrating peptides can transport therapeutic agents across plasma membranes but barely across the blood-brain barrier. Here the authors develop a peptide that can enter the brain, and show that its fusion to immunomodulatory protein ctCTLA-4 is effective in a mouse model of multiple sclerosis.
- Sangho Lim
- , Won-Ju Kim
- & Je-Min Choi