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The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.
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Aprendizaje Profundo , Diagnóstico por Imagen , Neumonía/diagnóstico , Niño , Humanos , Redes Neurales de la Computación , Neumonía/diagnóstico por imagen , Curva ROC , Reproducibilidad de los Resultados , Tomografía de Coherencia ÓpticaRESUMEN
Nanoparticles coated with natural cell membranes have emerged as a promising class of biomimetic nanomedicine with significant clinical potential. Among them, macrophage membrane-coated nanoparticles hold particular appeal due to their versatility in drug delivery and biological neutralization applications. This study employs a genetic engineering approach to enhance their in vivo residence times, aiming to further improve their performance. Specifically, macrophages are engineered to express proline-alanine-serine (PAS) peptide chains, which provide additional protection against opsonization and phagocytosis. The resulting modified nanoparticles demonstrate prolonged residence times when administered intravenously or introduced intratracheally, surpassing those coated with the wild-type membrane. The longer residence times also contribute to enhanced nanoparticle efficacy in inhibiting inflammatory cytokines in mouse models of lipopolysaccharide-induced lung injury and sublethal endotoxemia, respectively. This study underscores the effectiveness of genetic modification in extending the in vivo residence times of macrophage membrane-coated nanoparticles. This approach can be readily extended to modify other cell membrane-coated nanoparticles toward more favorable biomedical applications.
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Sistemas de Liberación de Medicamentos , Nanopartículas , Ratones , Animales , Sistemas de Liberación de Medicamentos/métodos , Macrófagos/metabolismo , Membrana Celular/metabolismo , CitoplasmaRESUMEN
Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s-1) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings highlight the attractive functions of algae-nanoparticle hybrid microrobots for the active in vivo delivery of therapeutics to the lungs in intensive care unit settings.
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Nanopartículas , Neumonía Bacteriana , Ratones , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Pseudomonas aeruginosa , PulmónRESUMEN
Anthrax infections caused by Bacillus anthracis are an ongoing bioterrorism and livestock threat worldwide. Current approaches for management, including extended passive antibody transfusion, antibiotics, and prophylactic vaccination, are often cumbersome and associated with low patient compliance. Here, we report on the development of an adjuvanted nanotoxoid vaccine based on macrophage membrane-coated nanoparticles bound with anthrax toxins. This design leverages the natural binding interaction of protective antigen, a key anthrax toxin, with macrophages. In a murine model, a single low-dose vaccination with the nanotoxoids generates long-lasting immunity that protects against subsequent challenge with anthrax toxins. Overall, this work provides a new approach to address the ongoing threat of anthrax outbreaks and bioterrorism by taking advantage of an emerging biomimetic nanotechnology.
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Vacunas contra el Carbunco , Carbunco , Toxinas Bacterianas , Animales , Humanos , Ratones , Carbunco/prevención & control , Antígenos Bacterianos , Bacillus anthracis , NanotecnologíaRESUMEN
Natural cell membranes derived from various cell sources have been successfully utilized to coat nanomaterials for functionalization. However, intracellular membranes from the organelles of eukaryotes remain unexplored. Herein, we choose mitochondrion as a representative cell organelle and coat outer mitochondrial membrane (OMM) from mouse livers onto nanoparticles and field-effect transistors (FETs) through a membrane vesicle-substrate fusion process. Polymeric nanoparticles coated with OMM (OMM-NPs) can bind with ABT-263, a B-cell lymphoma protein 2 (Bcl-2) inhibitor that targets the OMM. As a result, OMM-NPs effectively protect the cells from ABT-263 induced cell death and apoptosis in vitro and attenuated ABT-263-induced thrombocytopenia in vivo. Meanwhile, FET sensors coated with OMM (OMM-FETs) can detect and distinguish anti-Bcl-2 antibody and small molecule agonists. Overall, these results show that OMM can be coated onto the surfaces of both nanoparticles and functional devices, suggesting that intracellular membranes can be used as coating materials for novel biointerfacing.
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Membranas Mitocondriales , Nanopartículas , Animales , Apoptosis , Membrana Celular , Ratones , Mitocondrias , Membranas Mitocondriales/metabolismoRESUMEN
Metal-organic-framework nanoparticles (MOF NPs) have been increasingly used to encapsulate therapeutic enzymes for delivery. To better interface these MOF NPs with biological systems, researchers have coated them with natural cell membranes, enabling biomimicking properties suitable for innovative biomedical applications. Herein, we report that the enzymatic activity of cell-membrane-coated MOF NPs can be significantly enhanced by reducing membrane cholesterol content. We demonstrate such cholesterol-enzymatic activity correlation using zeolitic imidazolate framework-8 MOF NPs to encapsulate catalase, horseradish peroxidase, and organophosphate hydrolase, respectively. MOF NPs coated with membranes of human red blood cells or macrophages show similar outcomes, illustrating the broad applicability of this finding. The mechanistic investigation further reveals that reducing cholesterol levels effectively enhances membrane permeability likely responsible for the increased enzymatic activity. These results also imply a facile approach to tailoring the enzymatic activity of cell-membrane-coated MOF NPs by simply tuning the membrane cholesterol level.
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Estructuras Metalorgánicas , Nanopartículas , Zeolitas , Membrana Celular/metabolismo , Humanos , Estructuras Metalorgánicas/metabolismoRESUMEN
There has been significant interest in developing cell membrane-coated nanoparticles due to their unique abilities of biomimicry and biointerfacing. As the technology progresses, it becomes clear that the application of these nanoparticles can be drastically broadened if additional functions beyond those derived from the natural cell membranes can be integrated. Herein, we summarize the most recent advances in the functionalization of cell membrane-coated nanoparticles. In particular, we focus on emerging methods, including (1) lipid insertion, (2) membrane hybridization, (3) metabolic engineering, and (4) genetic modification. These approaches contribute diverse functions in a nondisruptive fashion while preserving the natural function of the cell membranes. They also improve on the multifunctional and multitasking ability of cell membrane-coated nanoparticles, making them more adaptive to the complexity of biological systems. We hope that these approaches will serve as inspiration for more strategies and innovations to advance cell membrane coating technology.
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Membrana Celular/química , Nanopartículas/química , Nanotecnología/métodosRESUMEN
Cellular binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mediated by its spike glycoprotein (S protein), which binds with not only the human angiotensin-converting enzyme 2 (ACE2) receptor but also glycosaminoglycans such as heparin. Cell membrane-coated nanoparticles ("cellular nanosponges") mimic the host cells to attract and neutralize SARS-CoV-2 through natural cellular receptors, leading to a broad-spectrum antiviral strategy. Herein, we show that increasing surface heparin density on the cellular nanosponges can promote their inhibition against SARS-CoV-2. Specifically, cellular nanosponges are made with azido-expressing host cell membranes followed by conjugating heparin to the nanosponge surfaces. Cellular nanosponges with a higher heparin density have a larger binding capacity with viral S proteins and a significantly higher inhibition efficacy against SARS-CoV-2 infectivity. Overall, surface glycan engineering of host-mimicking cellular nanosponges is a facile method to enhance SARS-CoV-2 inhibition. This approach can be readily generalized to promote the inhibition of other glycan-dependent viruses.
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Tratamiento Farmacológico de COVID-19 , Heparina/administración & dosificación , Nanoestructuras/uso terapéutico , Polisacáridos/administración & dosificación , SARS-CoV-2/metabolismo , COVID-19/virología , Heparina/metabolismo , Humanos , Polisacáridos/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19), caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst pandemic disease of the current millennium. To address this crisis, therapeutic nanoparticles, including inorganic nanoparticles, lipid nanoparticles, polymeric nanoparticles, virus-like nanoparticles, and cell membrane-coated nanoparticles, have all offered compelling antiviral strategies. This article reviews these strategies in three categories: (1) nanoparticle-enabled detection of SARS-CoV-2, (2) nanoparticle-based treatment for COVID-19, and (3) nanoparticle vaccines against SARS-CoV-2. We discuss how nanoparticles are tailor-made to biointerface with the host and the virus in each category. For each nanoparticle design, we highlight its structure-function relationship that enables effective antiviral activity. Overall, nanoparticles bring numerous new opportunities to improve our response to the current COVID-19 pandemic and enhance our preparedness for future viral outbreaks.
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Therapeutic enzymes used for genetic disorders or metabolic diseases oftentimes suffer from suboptimal pharmacokinetics and stability. Nanodelivery systems have shown considerable promise for improving the performance of enzyme therapies. Here, we develop a cell membrane-camouflaged metal-organic framework (MOF) system with enhanced biocompatibility and functionality. The MOF core can efficiently encapsulate enzymes while maintaining their bioactivity. After the introduction of natural cell membrane coatings, the resulting nanoformulations can be safely administered in vivo. The surface receptors on the membrane can also provide additional functionalities that synergize with the encapsulated enzyme to target disease pathology from multiple dimensions. Employing uricase as a model enzyme, we demonstrate the utility of this approach in multiple animal disease models. The results support the use of cell membrane-coated MOFs for enzyme delivery, and this strategy could be leveraged to improve the usefulness of enzyme-based therapies for managing a wide range of important human health conditions.
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Membrana Celular , Enzimas/administración & dosificación , Estructuras Metalorgánicas , Nanopartículas , Animales , Sistemas de Liberación de Medicamentos , HumanosRESUMEN
An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , ADN Tumoral Circulante , Metilación de ADN , Neoplasias Hepáticas , Modelos Biológicos , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Masculino , PronósticoRESUMEN
The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.
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Factor H de Complemento/genética , Degeneración Macular/genética , Fosfolípidos/química , Anciano de 80 o más Años , Angiografía/métodos , Animales , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Drusas del Disco Óptico/metabolismo , Oxígeno/químicaRESUMEN
Since their initial development, cell membrane-coated nanoparticles (CNPs) have become increasingly popular in the biomedical field. Despite their inherent versatility and ability to enable complex biological applications, there is considerable interest in augmenting the performance of CNPs through the introduction of additional functionalities. Here we demonstrate a genetic-engineering-based modular approach to CNP functionalization that can encompass a wide range of ligands onto the nanoparticle surface. The cell membrane coating is engineered to express a SpyCatcher membrane anchor that can readily form a covalent bond with any moiety modified with SpyTag. To demonstrate the broad utility of this technique, three unique targeted CNP formulations are generated using different classes of targeting ligands, including a designed ankyrin repeat protein, an affibody and a single-chain variable fragment. In vitro, the modified nanoparticles exhibit enhanced affinity towards cell lines overexpressing the cognate receptors for each ligand. When formulated with a chemotherapeutic payload, the modularly functionalized nanoparticles display strong targeting ability and growth suppression in a murine tumour xenograft model of ovarian cancer. Our data suggest genetic engineering offers a feasible approach for accelerating the development of multifunctional CNPs for a broad range of biomedical applications.
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Ingeniería Genética , Nanopartículas , Humanos , Animales , Ratones , Línea Celular , Membrana Celular , Nanopartículas/químicaRESUMEN
Cytokines have been identified as key contributors to the development of inflammatory bowel disease (IBD), yet conventional treatments often prove inadequate and carry substantial side effects. Here, we present an innovative biohybrid robotic system, termed "algae-MΦNP-robot," for addressing IBD by actively neutralizing colonic cytokine levels. Our approach combines moving green microalgae with macrophage membrane-coated nanoparticles (MΦNPs) to efficiently capture proinflammatory cytokines "on the fly." The dynamic algae-MΦNP-robots outperformed static counterparts by enhancing cytokine removal through continuous movement, better distribution, and extended retention in the colon. This system is encapsulated in an oral capsule, which shields it from gastric acidity and ensures functionality upon reaching the targeted disease site. The resulting algae-MΦNP-robot capsule effectively regulated cytokine levels, facilitating the healing of damaged epithelial barriers. It showed markedly improved prevention and treatment efficacy in a mouse model of IBD and demonstrated an excellent biosafety profile. Overall, our biohybrid algae-MΦNP-robot system offers a promising and efficient solution for IBD, addressing cytokine-related inflammation effectively.
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Colon , Citocinas , Enfermedades Inflamatorias del Intestino , Nanopartículas , Robótica , Animales , Citocinas/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Robótica/instrumentación , Ratones , Humanos , Macrófagos/metabolismo , Mucosa Intestinal/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Masculino , Diseño de Equipo , EpitelioRESUMEN
Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract disorder characterized by uncontrolled inflammatory responses to the disrupted intestinal epithelial barrier and gut microbiome dysbiosis. Currently available small-molecule immunosuppressive agents and anticytokine biologics show limited potency, mainly due to the complexity of the inflammatory network involved in IBD. Here, we develop an oral formulation of macrophage membrane-coated nanoparticles capsulated in enteric polymer-coated gelatin capsules (denoted "cp-MΦ-NPs") for IBD treatment. The capsules protect the nanoparticles from gastric degradation and allow for targeted delivery to the colon. At the inflamed colon, cp-MΦ-NPs act as macrophage decoys that bind and neutralize pro-inflammatory cytokines. The in vivo treatment efficacy of cp-MΦ-NPs is tested in a mouse model of dextran sulfate sodium-induced colitis. In both prophylactic and delayed treatment regimens, the oral delivery of cp-MΦ-NPs significantly alleviates IBD severity, reflected by reduced intestinal inflammation and intestinal barrier restoration. Overall, cp-MΦ-NPs provide a biomimetic nanomedicine strategy for the treatment of IBD.
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Colitis , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Cápsulas , Mucosa Intestinal , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Colitis/inducido químicamente , Intestinos , Colon/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Botulinum toxin (BoNT) is a potent neurotoxin that poses a significant threat as a biowarfare weapon and a potential bioterrorist tool. Currently, there is a lack of effective countermeasures to combat BoNT intoxication in the event of a biological attack. Here, we report on a novel solution by combining cell metabolic engineering with cell membrane coating nanotechnology, resulting in the development of glycan-modified cellular nanosponges that serve as a biomimetic and broad-spectrum BoNT detoxification strategy. Specifically, we increase the expression levels of gangliosides on THP-1 cells through metabolic engineering, and then collect the modified THP-1 cell membrane and coat it onto synthetic polymeric cores, creating cellular nanosponges that closely mimic host cells. Our findings demonstrate that higher levels of gangliosides on the cellular nanosponges result in greater binding capacities with BoNT. The glycan-modified cellular nanosponges exhibit superior efficacy in neutralizing BoNT cytotoxicity in vitro when compared to their unmodified counterparts. In a mouse model of BoNT intoxication, the glycan-modified cellular nanosponges show more pronounced survival benefits when administered both as a treatment and a preventative regimen. These results highlight the potential of cellular nanosponges, especially when modified with glycans, as a promising countermeasure platform against BoNT and related clostridial toxins.
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Toxinas Botulínicas , Ratones , Animales , Membrana Celular/metabolismo , Gangliósidos/metabolismo , PolisacáridosRESUMEN
Neurotoxins attack and destruct the nervous system, which can cause serious health problems and security threats. Existing detoxification approaches, such as antibodies and small molecule antidotes, rely on neurotoxin's molecular structure as design cues and require toxin-specific development for each type of toxins. However, the enormous diversity of neurotoxins makes such structure-based development of antitoxin particularly challenging and inefficient. Here, we report on the development and use of neuronal membrane-coated nanosponges (denoted "Neuron-NS") as an effective approach to detoxifying neurotoxins. Specifically, Neuron-NS act as neuron decoys to lure neurotoxins, bind with and neutralize the toxins, and thus block them from attacking the host neuron cells. These nanosponges detoxify neurotoxins regardless of their molecular structures and therefore can overcome the challenge posed by toxin structural diversity. In the study, we fabricate Neuron-NS by coating the membrane of Neuro-2a cells onto polymeric cores. Meanwhile, we select tetrodotoxin (TTX) as a model neurotoxin and demonstrate the detoxification efficacy of the Neuron-NS in a cytotoxicity assay, a calcium flux assay, and a cell osmotic swelling assay in vitro. Additionally, in mouse models of TTX intoxication, the Neuron-NS significantly enhance mouse survival in therapeutic and prophylactic regimens without showing acute toxicity. Overall, the Neuron-NS contribute to the current detoxification arsenal with the potential to treat various injuries and diseases caused by neurotoxins.
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Neuronas , Neurotoxinas , Ratones , Animales , Neurotoxinas/toxicidad , Neurotoxinas/química , AntídotosRESUMEN
Biological neutralization represents a general strategy that deploys therapeutic agents to bind with harmful molecules or infectious pathogens, block their bioactivity, and thus prevent them from causing the diseases. Here, a comprehensive review of using cell-membrane-coated nanoparticles, namely "cellular nanosponges," as host decoys for a wide range of biological neutralization applications is provided. Compared to traditional neutralization strategies, the cellular nanosponges stand out by mimicking susceptible host cells rather than accommodating the structures of the causative agents for the design of therapeutics. As all pathological agents must interact with host cells for bioactivity, nanosponges bypass the diversity of these agents and create function-driven and broad-spectrum neutralization solutions. The review focuses on the recent progress of using this new nanomedicine platform for neutralization against five primary pathological agents, including bacterial toxins, chemical toxicants, inflammatory cytokines, pathological antibodies, and viruses. Existing studies have established cellular nanosponges as versatile tools for biological neutralization. A thorough review of the cellular nanosponge technology is expected to inspire more refined cellular nanosponge designs and unique neutralization applications to address unsolved medical problems.
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Toxinas Bacterianas , Nanopartículas , Membrana Celular , Nanopartículas/químicaRESUMEN
The use of micromotors for active drug delivery via oral administration has recently gained considerable interest. However, efficient motor-assisted delivery into the gastrointestinal (GI) tract remains challenging, owing to the short propulsion lifetime of currently used micromotor platforms. Here, we report on an efficient algae-based motor platform, which takes advantage of the fast and long-lasting swimming behavior of natural microalgae in intestinal fluid to prolong local retention within the GI tract. Fluorescent dye or cell membrane-coated nanoparticle functionalized algae motors were further embedded inside a pH-sensitive capsule to enhance delivery to the small intestines. In vitro, the algae motors displayed a constant motion behavior in simulated intestinal fluid after 12 hours of continuous operation. When orally administered in vivo into mice, the algae motors substantially improved GI distribution of the dye payload compared with traditional magnesium-based micromotors, which are limited by short propulsion lifetimes, and they also enhanced retention of a model chemotherapeutic payload in the GI tract compared with a passive nanoparticle formulation. Overall, combining the efficient motion and extended lifetime of natural algae-based motors with the protective capabilities of oral capsules results in a promising micromotor platform capable of achieving greatly improved cargo delivery in GI tissue for practical biomedical applications.
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Colorantes Fluorescentes , Magnesio , Animales , Cápsulas , Sistemas de Liberación de Medicamentos , Tracto Gastrointestinal , RatonesRESUMEN
The function of robots in extreme environments is regarded as one of the major challenges facing robotics. Here, we demonstrate that acidophilic microalgae biomotors can maintain their swimming behavior over long periods of time in the harsh acidic environment of the stomach, thus enabling them to be applied for gastrointestinal (GI) delivery applications. The biomotors can also be functionalized with a wide range of cargos, ranging from small molecules to nanoparticles, without compromising their ability to self-propel under extreme conditions. Successful GI delivery of model payloads after oral administration of the acidophilic algae motors is confirmed using a murine model. By tuning the surface properties of cargos, it is possible to modulate their precise GI localization. Overall, our findings indicate that multifunctional acidophilic algae-based biomotors offer distinct advantages compared to traditional biohybrid platforms and hold great potential for GI-related biomedical applications.