RESUMEN
In vaccinology, both mRNA-based delivery of genes encoding antigens as well as nanoparticle-based vaccines have shown great promise in tackling challenging pathogens. In this issue of Cell, Hoffmann et al. combine these two approaches, harnessing the same cellular pathway hijacked by many viruses to boost immune responses to SARS-CoV-2 vaccination.
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Vacunas contra la COVID-19 , Nanopartículas , Humanos , Anticuerpos Antivirales , División Celular , COVID-19 , SARS-CoV-2RESUMEN
In vivo gene editing therapies offer the potential to treat the root causes of many genetic diseases. Realizing the promise of therapeutic in vivo gene editing requires the ability to safely and efficiently deliver gene editing agents to relevant organs and tissues in vivo. Here, we review current delivery technologies that have been used to enable therapeutic in vivo gene editing, including viral vectors, lipid nanoparticles, and virus-like particles. Since no single delivery modality is likely to be appropriate for every possible application, we compare the benefits and drawbacks of each method and highlight opportunities for future improvements.
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Edición Génica , Nanopartículas , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Terapia Genética/métodos , Vectores Genéticos , LiposomasRESUMEN
A game-changing intervention in the COVID-19 pandemic has been the rapid implementation of highly effective vaccines against SARS-CoV-2. The 2022 Canada Gairdner International Award recognizes Pieter Cullis, Katalin Karikó, and Drew Weissman "for their pioneering work developing nucleoside-modified mRNA and lipid nanoparticle (LNP) drug delivery: the foundational technologies for the highly effective COVID-19 mRNA vaccines." Cell editor Cheri Sirois caught up with Pieter to discuss how a long interest in basic and applied questions in lipid biology led to this fortuitous collaboration. Excerpts of the conversation are presented below.
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Vacunas contra la COVID-19 , Liposomas , Nanopartículas , COVID-19/prevención & control , Humanos , Lípidos , Pandemias/prevención & control , SARS-CoV-2RESUMEN
The bedrock of drug discovery and a key tool for understanding cellular function and drug mechanisms of action is the structure determination of chemical compounds, peptides, and proteins. The development of new structure characterization tools, particularly those that fill critical gaps in existing methods, presents important steps forward for structural biology and drug discovery. The emergence of microcrystal electron diffraction (MicroED) expands the application of cryo-electron microscopy to include samples ranging from small molecules and membrane proteins to even large protein complexes using crystals that are one-billionth the size of those required for X-ray crystallography. This review outlines the conception, achievements, and exciting future trajectories for MicroED, an important addition to the existing biophysical toolkit.
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Microscopía por Crioelectrón/métodos , Descubrimiento de Drogas/métodos , Nanopartículas/química , Proteínas/química , Microscopía por Crioelectrón/instrumentación , Cristalización , Electrones , Microscopía Electrónica de Transmisión/instrumentación , Microscopía Electrónica de Transmisión/métodos , Flujo de TrabajoRESUMEN
A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Proteína gp41 de Envoltorio del VIH , Infecciones por VIH , VIH-1 , Macaca mulatta , Animales , Humanos , Proteína gp41 de Envoltorio del VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Ratones , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Vacunación , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos B/inmunología , Nanopartículas/química , Femenino , Regiones Determinantes de Complementariedad/inmunología , Epítopos/inmunologíaRESUMEN
Electron cryotomography (cryoET), an electron cryomicroscopy (cryoEM) modality, has changed our understanding of biological function by revealing the native molecular details of membranes, viruses, and cells. However, identification of individual molecules within tomograms from cryoET is challenging because of sample crowding and low signal-to-noise ratios. Here, we present a tagging strategy for cryoET that precisely identifies individual protein complexes in tomograms without relying on metal clusters. Our method makes use of DNA origami to produce "molecular signposts" that target molecules of interest, here via fluorescent fusion proteins, providing a platform generally applicable to biological surfaces. We demonstrate the specificity of signpost origami tags (SPOTs) in vitro as well as their suitability for cryoET of membrane vesicles, enveloped viruses, and the exterior of intact mammalian cells.
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Membrana Celular/ultraestructura , Microscopía por Crioelectrón , ADN/ultraestructura , Tomografía con Microscopio Electrónico , Animales , Aptámeros de Nucleótidos/química , Fenómenos Biofísicos , Línea Celular , Femenino , Fluorescencia , Humanos , Nanopartículas/ultraestructuraRESUMEN
We describe an approach to study the conformation of individual proteins during single particle tracking (SPT) in living cells. "Binder/tag" is based on incorporation of a 7-mer peptide (the tag) into a protein where its solvent exposure is controlled by protein conformation. Only upon exposure can the peptide specifically interact with a reporter protein (the binder). Thus, simple fluorescence localization reflects protein conformation. Through direct excitation of bright dyes, the trajectory and conformation of individual proteins can be followed. Simple protein engineering provides highly specific biosensors suitable for SPT and FRET. We describe tagSrc, tagFyn, tagSyk, tagFAK, and an orthogonal binder/tag pair. SPT showed slowly diffusing islands of activated Src within Src clusters and dynamics of activation in adhesions. Quantitative analysis and stochastic modeling revealed in vivo Src kinetics. The simplicity of binder/tag can provide access to diverse proteins.
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Técnicas Biosensibles , Péptidos/química , Imagen Individual de Molécula , Animales , Adhesión Celular , Línea Celular , Supervivencia Celular , Embrión de Mamíferos/citología , Activación Enzimática , Fibroblastos/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Cinética , Ratones , Nanopartículas/química , Conformación Proteica , Familia-src Quinasas/metabolismoRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.
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Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , Macaca fascicularis , Glicoproteína de la Espiga del Coronavirus/química , Animales , Anticuerpos Neutralizantes , Linfocitos B/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Nanopartículas/administración & dosificación , Conejos , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/sangre , Linfocitos T/inmunología , Carga ViralRESUMEN
Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Adenoviridae/genética , Animales , Antígenos Virales/genética , Materiales Biocompatibles , COVID-19/virología , Sistemas de Liberación de Medicamentos/métodos , Vectores Genéticos/inmunología , Humanos , Inmunogenicidad Vacunal , Liposomas , Nanopartículas , ARN Mensajero/síntesis química , ARN Mensajero/inmunología , Vacunas de ARNmRESUMEN
Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
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Tratamiento Farmacológico de COVID-19 , Virus Interferentes Defectuosos/metabolismo , Replicación Viral/efectos de los fármacos , Animales , Antivirales/farmacología , COVID-19/metabolismo , Línea Celular , Chlorocebus aethiops , Medios de Cultivo Condicionados/farmacología , Virus Interferentes Defectuosos/patogenicidad , Sistemas de Liberación de Medicamentos/métodos , Células Epiteliales , Humanos , Masculino , Mesocricetus , Nanopartículas/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Células VeroRESUMEN
The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74,000 participants (half receiving placebo) after intramuscular delivery of two shots, 3-4 weeks apart. To view this Bench to Bedside, open or download the PDF.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , COVID-19/virología , Sistemas de Liberación de Medicamentos/métodos , Humanos , Liposomas , Nanopartículas , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento , Vacunas de ARNmRESUMEN
Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8.0, similar structures of NPC1 were obtained in nanodiscs and in detergent at resolutions of 3.6 Å and 3.0 Å, respectively. A tunnel connecting the N-terminal domain (NTD) and the transmembrane sterol-sensing domain (SSD) was unveiled. At pH 5.5, the NTD exhibits two conformations, suggesting the motion for cholesterol delivery to the tunnel. A putative cholesterol molecule is found at the membrane boundary of the tunnel, and TM2 moves toward formation of a surface pocket on the SSD. Finally, the structure of the NPC1-NPC2 complex at 4.0 Å resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).
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Colesterol/metabolismo , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisosomas/metabolismo , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Modelos Moleculares , Nanopartículas/química , Nanopartículas/ultraestructura , Proteína Niemann-Pick C1 , Dominios Proteicos , Homología Estructural de Proteína , Relación Estructura-ActividadRESUMEN
A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Nanopartículas/química , Dominios Proteicos/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Vacunación , Adolescente , Adulto , Anciano , Animales , COVID-19/virología , Chlorocebus aethiops , Estudios de Cohortes , Epítopos/inmunología , Femenino , Células HEK293 , Humanos , Macaca nemestrina , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero , Adulto JovenRESUMEN
There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.
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ARN Mensajero/genética , ARN Viral/genética , Vacunas Sintéticas/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , Vacunas contra la COVID-19 , Chlorocebus aethiops , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Femenino , Células HEK293 , Células HeLa , Humanos , Inmunogenicidad Vacunal , Inyecciones Intramusculares , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos ICR , Nanopartículas/química , ARN Mensajero/metabolismo , ARN Viral/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Células TH1/inmunología , Potencia de la Vacuna , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Células Vero , Vacunas Virales/administración & dosificación , Vacunas Virales/genéticaRESUMEN
In this issue, Marcandalli et al. (2019) report a self-assembling nanoparticle bearing an antigen from respiratory syncytial virus. This is the first time the structure, stability, and adjuvanticity of an antigen have been rationally designed at the atomic level and incorporated in one vaccine.
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Nanopartículas , Vacunas , Anticuerpos Neutralizantes , Antígenos , Virus Sincitiales RespiratoriosRESUMEN
Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses â¼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.
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Anticuerpos Neutralizantes/inmunología , Virus Sincitiales Respiratorios/inmunología , Vacunación/métodos , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/inmunología , Caveolina 1 , Línea Celular , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/uso terapéutico , Cultivo Primario de Células , Virus Sincitiales Respiratorios/patogenicidad , Vacunas/inmunología , Proteínas Virales de Fusión/inmunología , Proteínas Virales de Fusión/metabolismo , Proteínas Virales de Fusión/fisiologíaRESUMEN
Mammals cannot see light over 700 nm in wavelength. This limitation is due to the physical thermodynamic properties of the photon-detecting opsins. However, the detection of naturally invisible near-infrared (NIR) light is a desirable ability. To break this limitation, we developed ocular injectable photoreceptor-binding upconversion nanoparticles (pbUCNPs). These nanoparticles anchored on retinal photoreceptors as miniature NIR light transducers to create NIR light image vision with negligible side effects. Based on single-photoreceptor recordings, electroretinograms, cortical recordings, and visual behavioral tests, we demonstrated that mice with these nanoantennae could not only perceive NIR light, but also see NIR light patterns. Excitingly, the injected mice were also able to differentiate sophisticated NIR shape patterns. Moreover, the NIR light pattern vision was ambient-daylight compatible and existed in parallel with native daylight vision. This new method will provide unmatched opportunities for a wide variety of emerging bio-integrated nanodevice designs and applications. VIDEO ABSTRACT.
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Nanopartículas/uso terapéutico , Células Fotorreceptoras de Vertebrados/fisiología , Visión Ocular/fisiología , Animales , Femenino , Rayos Infrarrojos , Inyecciones/métodos , Luz , Masculino , Mamíferos/fisiología , Ratones , Ratones Endogámicos C57BL , Opsinas/metabolismo , Retina/metabolismo , Retina/fisiología , Células Fotorreceptoras Retinianas Conos/fisiología , Visión Ocular/genéticaRESUMEN
Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Factor Nuclear 1-alfa del Hepatocito/análisis , Nanopartículas , Animales , Presentación de Antígeno , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Femenino , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , VacunaciónRESUMEN
Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation.
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Citoplasma/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Difusión , Células HEK293 , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Nanopartículas/química , Nanopartículas/metabolismo , Tamaño de la Partícula , Plásmidos/genética , Plásmidos/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Reología , Ribosomas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/antagonistas & inhibidores , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (â¼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.