271 research outputs found
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Selective cell death of latently HIV-infected CD4+ T cells mediated by autosis inducing nanopeptides.
Despite significant advances in the treatment of human immunodeficiency virus type-1 (HIV) infection, antiretroviral therapy only suppresses viral replication but is unable to eliminate infection. Thus, discontinuation of antiretrovirals results in viral reactivation and disease progression. A major reservoir of HIV latent infection resides in resting central memory CD4+ T cells (TCM) that escape clearance by current therapeutic regimens and will require novel strategies for elimination. Here, we evaluated the therapeutic potential of autophagy-inducing peptides, Tat-Beclin 1 and Tat-vFLIP-α2, which can induce a novel Na+/K+-ATPase dependent form of cell death (autosis), to kill latently HIV-infected TCM while preventing virologic rebound. In this study, we encapsulated autophagy inducing peptides into biodegradable lipid-coated hybrid PLGA (poly lactic-co-glycolic acid) nanoparticles for controlled intracellular delivery. A single dose of nanopeptides was found to eliminate latent HIV infection in an in vitro primary model of HIV latency and ex vivo using resting CD4+ T cells obtained from peripheral blood mononuclear cells of HIV-infected patients on antiretroviral with fully suppressed virus for greater than 12 months. Notably, increased LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase activity characteristic of autosis, were detected in nanopeptide treated latently HIV-infected cells compared to untreated uninfected or infected cells. Nanopeptide-induced cell death could be reversed by knockdown of autophagy proteins, ATG5 and ATG7, and inhibition or knockdown of Na+/K+-ATPase. Importantly, viral rebound was not detected following the induction of the Na+/K+-ATPase dependent form of cell death induced by the Tat-Beclin 1 and Tat-vFLIP-α2 nanopeptides. These findings provide a novel strategy to eradicate HIV latently infected resting memory CD4+ T cells, the major reservoir of HIV latency, through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells
Artificial Micromotors in the Mouse’s Stomach: A Step toward in Vivo Use of Synthetic Motors
Artificial micromotors, operating on locally supplied fuels and performing complex tasks, offer great potential for diverse biomedical applications, including autonomous delivery and release of therapeutic payloads and cell manipulation. Various types of synthetic motors, utilizing different propulsion mechanisms, have been fabricated to operate in biological matrices. However, the performance of these man-made motors has been tested exclusively under in vitro conditions (outside the body); their behavior and functionalities in an in vivo environment (inside the body) remain unknown. Herein, we report an in vivo study of artificial micromotors in a living organism using a mouse model. Such in vivo evaluation examines the distribution, retention, cargo delivery, and acute toxicity profile of synthetic motors in mouse stomach via oral administration. Using zinc-based micromotors as a model, we demonstrate that the acid-driven propulsion in the stomach effectively enhances the binding and retention of the motors as well as of cargo payloads on the stomach wall. The body of the motors gradually dissolves in the gastric acid, autonomously releasing their carried payloads, leaving nothing toxic behind. This work is anticipated to significantly advance the emerging field of nano/micromotors and to open the door to in vivo evaluation and clinical applications of these synthetic motors
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Macrophage-Mimicking Cellular Nanoparticles Scavenge Proinflammatory Cytokines in Specimens of Patients with Inflammatory Disorders.
Effectively neutralizing inflammatory cytokines is crucial for managing a variety of inflammatory disorders. Current techniques that target only a subset of cytokines often fall short due to the intricate nature of redundant and compensatory cytokine networks. A promising solution to this challenge is using cell membrane-coated nanoparticles (CNPs). These nanoparticles replicate the complex interactions between cells and cytokines observed in disease pathology, providing a potential avenue for multiplex cytokine scavenging. While the development of CNPs using experimental animal models has shown great promise, their effectiveness in scavenging multiple cytokines in human diseases has yet to be demonstrated. To bridge this gap, this study selected macrophage membrane-coated CNPs (MФ-CNPs) and assessed their ability to scavenge inflammatory cytokines in serum samples from patients with COVID-19, sepsis, acute pancreatitis, or type-1 diabetes, along with synovial fluid samples from patients with rheumatoid arthritis. The results show that MФ-CNPs effectively scavenge critical inflammatory cytokines, including interleukin (IL)-6, IL-8, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, in a dose-dependent manner. Overall, this study demonstrates MФ-CNPs as a multiplex cytokine scavenging formulation with promising applications in clinical settings to treat a range of inflammatory disorders
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Monitoring of the central blood pressure waveform via a conformal ultrasonic device.
Continuous monitoring of the central-blood-pressure waveform from deeply embedded vessels, such as the carotid artery and jugular vein, has clinical value for the prediction of all-cause cardiovascular mortality. However, existing non-invasive approaches, including photoplethysmography and tonometry, only enable access to the superficial peripheral vasculature. Although current ultrasonic technologies allow non-invasive deep-tissue observation, unstable coupling with the tissue surface resulting from the bulkiness and rigidity of conventional ultrasound probes introduces usability constraints. Here, we describe the design and operation of an ultrasonic device that is conformal to the skin and capable of capturing blood-pressure waveforms at deeply embedded arterial and venous sites. The wearable device is ultrathin (240 μm) and stretchable (with strains up to 60%), and enables the non-invasive, continuous and accurate monitoring of cardiovascular events from multiple body locations, which should facilitate its use in a variety of clinical environments
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Group A Streptococcal S Protein Utilizes Red Blood Cells as Immune Camouflage and Is a Critical Determinant for Immune Evasion.
Group A Streptococcus (GAS) is a human-specific pathogen that evades the host immune response through the elaboration of multiple virulence factors. Although many of these factors have been studied, numerous proteins encoded by the GAS genome are of unknown function. Herein, we characterize a biomimetic red blood cell (RBC)-captured protein of unknown function-annotated subsequently as S protein-in GAS pathophysiology. S protein maintains the hydrophobic properties of GAS, and its absence reduces survival in human blood. S protein facilitates GAS coating with lysed RBCs to promote molecular mimicry, which increases virulence in vitro and in vivo. Proteomic profiling reveals that the removal of S protein from GAS alters cellular and extracellular protein landscapes and is accompanied by a decrease in the abundance of several key GAS virulence determinants. In vivo, the absence of S protein results in a striking attenuation of virulence and promotes a robust immune response and immunological memory
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Immunocompatibility properties of lipid–polymer hybrid nanoparticles with heterogeneous surface functional groups
Here we report the immunological characterization of lipid-polymer hybrid nanoparticles (NPs) and propose a method to control the levels of complement activation induced by these NPs. This method consists of the highly specific modification of the NP surface with methoxyl, carboxyl, and amine groups. Hybrid NPs with methoxyl surface groups induced the lowest complement activation, whereas the NPs with amine surface groups induced the highest activation. All possible combinations among carboxyl, amine, and methoxyl groups also activated the complement system to a certain extent. All types of NPs activated the complement system primarily via the alternative pathway rather than the lectin pathway The classical pathway was activated to a very small extent by the NPs with carboxyl and amine surface groups. Human serum and plasma protein binding studies showed that these NPs had different protein binding patterns. Studies of both complement activation and coagulation activation suggested that NPs with methoxyl surface groups might be an ideal candidate for drug delivery applications, since they are not likely to cause any immunological adverse reaction in the human body
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Turning Erythrocytes into Functional Micromotors
Attempts to apply artificial nano/micromotors for diverse biomedical applications have inspired a variety of strategies for designing motors with diverse propulsion mechanisms and functions. However, existing artificial motors are made exclusively of synthetic materials, which are subject to serious immune attack and clearance upon entering the bloodstream. Herein we report an elegant approach that turns natural red blood cells (RBCs) into functional micromotors with the aid of ultrasound propulsion and magnetic guidance. Iron oxide nanoparticles are loaded into the RBCs, where their asymmetric distribution within the cells results in a net magnetization, thus enabling magnetic alignment and guidance under acoustic propulsion. The RBC motors display efficient guided and prolonged propulsion in various biological fluids, including undiluted whole blood. The stability and functionality of the RBC motors, as well as the tolerability of regular RBCs to the ultrasound operation, are carefully examined. Since the RBC motors preserve the biological and structural features of regular RBCs, these motors possess a wide range of antigenic, transport, and mechanical properties that common synthetic motors cannot achieve and thus hold considerable promise for a number of practical biomedical uses
Fully Loaded Micromotors for Combinatorial Delivery and Autonomous Release of Cargoes
Integrating functional self-propelled Zinc micromotors are created by coupÂling electrodeposition with hard dual-templating synthesis. The micromotors concurrently possess four robust functions including a remarkably high loading capacity, combinatorial delivery of cargoes, autonomous release of encapsulated payloads, and self-destruction. This concept could be expanded to simultaneous encapsulation of various payloads for different functionalities such as therapy, diagnostics, and imaging
Artificial Micromotors in the Mouse’s Stomach: A Step toward in Vivo Use of Synthetic Motors
Artificial micromotors, operating on locally supplied fuels and performing complex tasks, offer great potential for diverse biomedical applications, including autonomous delivery and release of therapeutic payloads and cell manipulation. Various types of synthetic motors, utilizing different propulsion mechanisms, have been fabricated to operate in biological matrices. However, the performance of these man-made motors has been tested exclusively under in vitro conditions (outside the body); their behavior and functionalities in an in vivo environment (inside the body) remain unknown. Herein, we report an in vivo study of artificial micromotors in a living organism using a mouse model. Such in vivo evaluation examines the distribution, retention, cargo delivery, and acute toxicity profile of synthetic motors in mouse stomach via oral administration. Using zinc-based micromotors as a model, we demonstrate that the acid-driven propulsion in the stomach effectively enhances the binding and retention of the motors as well as of cargo payloads on the stomach wall. The body of the motors gradually dissolves in the gastric acid, autonomously releasing their carried payloads, leaving nothing toxic behind. This work is anticipated to significantly advance the emerging field of nano/micromotors and to open the door to in vivo evaluation and clinical applications of these synthetic motors
Fully Loaded Micromotors for Combinatorial Delivery and Autonomous Release of Cargoes
Integrating functional self-propelled Zinc micromotors are created by coupÂling electrodeposition with hard dual-templating synthesis. The micromotors concurrently possess four robust functions including a remarkably high loading capacity, combinatorial delivery of cargoes, autonomous release of encapsulated payloads, and self-destruction. This concept could be expanded to simultaneous encapsulation of various payloads for different functionalities such as therapy, diagnostics, and imaging
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