RESUMEN
Two-dimension graphene oxide (GO) nanosheets with high and low serum protein binding profiles (high/low hard-bound protein corona/HChigh/low) are used in this study as model materials and screening tools to investigate the underlying roles of the protein corona on nanomaterial toxicities in vivo. We proposed that the in vivo biocompatibility/nanotoxicity of GO is protein corona-dependent and host immunity-dependent. The hypothesis was tested by injecting HChigh/low GO nanosheets in immunocompetent ICR/CD1 and immunodeficient NOD-scid II2rγnull mice and performed histopathological and hematological evaluation studies on days 1 and 14 post-injection. HClow GO induced more severe acute lung injury compared to HChigh GO in both immunocompetent and immunodeficient mice, with the effect being particularly pronounced in immunocompetent animals. Additionally, HClow GO caused more significant liver injury in both types of mice, with immunodeficient mice being more susceptible to its hepatotoxic effects. Moreover, administration of HClow GO resulted in increased hematological toxicity and elevated levels of serum pro-inflammatory cytokines in immunocompromised and immunocompetent mice, respectively. Correlation studies were conducted to explore the impact of distinct protein corona compositions on resulting toxicities in both immunocompetent and immunodeficient mice. This facilitated the identification of consistent patterns, aligning with those observed in vitro, thus indicating a robust in vitro-in vivo correlation. This research will advance our comprehension of how hard corona proteins interact with immune cells, leading to toxicity, and will facilitate the development of improved immune-modulating nanomaterials for therapeutic purposes.
Asunto(s)
Grafito , Ratones Endogámicos ICR , Nanoestructuras , Corona de Proteínas , Animales , Grafito/química , Grafito/toxicidad , Ratones , Corona de Proteínas/química , Corona de Proteínas/inmunología , Nanoestructuras/química , Nanoestructuras/toxicidad , Ratones SCID , Ratones Endogámicos NODRESUMEN
Weak interactions play an important role in soft corona (SC) formation and thus help in evaluating the biological fate of the nanoparticles (NPs). Preadsorption of specific proteins on the NP surface, leading to SC formation, has been found to help NPs in evading immunosurveillance. However, the role of different preadsorbed biomolecules in determining the NP pathophysiology and cellular association, upon their re-exposure to in vivo conditions, still remains elusive. Here, differently charged gold NPs were precoated with two different blood components, viz. red blood cells and human serum albumin protein, and these were then re-exposed to human serum. Cloaking NPs with protein improved the NP colloidal stability and other physico-chemical properties along with increased cellular association. Detailed proteomic analysis suggested that protein-camouflaged NPs showed a decrease in immune-responsive proteins compared to their bare counterparts. Further, it was also observed that the secondary protein signature on the NP surface was governed by primary protein coating; however, the event was more or less NP charge-independent. This study will pave the path for future strategies to make NPs invincible to the immunosurveillance system of the body.
Asunto(s)
Materiales Biocompatibles/química , Oro/química , Nanopartículas del Metal/química , Corona de Proteínas/química , Oro/inmunología , Células HEK293 , Humanos , Ensayo de Materiales , Estructura Molecular , Monitorización Inmunológica , Tamaño de la Partícula , Corona de Proteínas/inmunología , Propiedades de SuperficieRESUMEN
The plasma proteins around nanoparticles (NPs) form an outer protein corona, significantly influencing the subsequent immune response. However, it was uncertain whether the protein corona around NPs influences immune response. This study clarified that the immune response mediated by the protein corona is greatly dependent on the type of plasma proteins surrounding the NPs. Structural changes in the unfolded protein corona elevated reactive oxygen species (ROS) levels and induced major proinflammatory cytokine release in both murine and human macrophage cell lines. In contrast, negligible structural changes in the protein corona provoke neither ROS production nor proinflammatory cytokine release. Furthermore, in vivo analysis confirms that a stimulated immune response by an unfolded protein corona triggers selective activation of innate and adaptive immunity in the spleen. Specifically, neutrophils, natural killer cells, and CD8+ T cells are overpopulated by unfolded protein corona structures surrounding nanotubes, whereas innate and adaptive immunologic responses are not triggered by a normal protein corona. In conclusion, highly unfolded protein corona structures are strongly correlated with subsequent activation of proinflammatory cytokines and innate immune responses; thus, the protein corona can be used in immune-enhancing therapy.
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Inmunidad Adaptativa/inmunología , Inmunidad Innata/inmunología , Corona de Proteínas/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Femenino , Humanos , Células Asesinas Naturales , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Nanotubos , Neutrófilos/inmunología , Especies Reactivas de Oxígeno/inmunologíaRESUMEN
Nanomedicine is an interdisciplinary field of research, comprising science, engineering, and medicine. Many are the clinical applications of nanomedicine, such as molecular imaging, medical diagnostics, targeted therapy, and image-guided surgery. Despite major advances during the past 20 years, many efforts must be done to understand the complex behavior of nanoparticles (NPs) under physiological conditions, the kinetic and thermodynamic principles, involved in the rational design of NP. Once administrated in physiological environment, NPs interact with biomolecules and they are surrounded by protein corona (PC) or biocorona. PC can trigger an immune response, affecting NPs toxicity and targeting capacity. This review aims to provide a detailed description of biocorona and of parameters that are able to control PC formation and composition. Indeed, the review provides an overview about the role of PC in the modulation of both cytotoxicity and immune response as well as in the control of targeting capacity.
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Nanomedicina , Nanopartículas/química , Corona de Proteínas/inmunología , Humanos , Cinética , Corona de Proteínas/química , TermodinámicaRESUMEN
Polysaccharide nanoparticles are promising materials in the wide range of disciplines such as medicine, nutrition, food production, agriculture, material science and others. They excel not only in their non-toxicity and biodegradability but also in their easy preparation. As well as inorganic particles, a protein corona (PC) around polysaccharide nanoparticles is formed in biofluids. Moreover, it has been considered that the overall response of the organism to nanoparticles presence depends on the PC. This review summarises scientific publications about the structural chemistry of polysaccharide nanoparticles and their impact on theranostic applications. Three strategies of implementation of the PC in theranostics have been discussed: I) Utilisation of the PC in therapy; II) How the composition of the PC is analysed for specific disease markers; III) How the formed PC can interact with the immune system and enhances the immunomodulation or immunoelimination. Thus, the findings from this review can contribute to improve the design of drug delivery systems. However, it is still necessary to elucidate the mechanisms of nano-bio interactions and discover new connections in nanoscale research.
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Nanopartículas/química , Polisacáridos/química , Corona de Proteínas , Nanomedicina Teranóstica/métodos , Adyuvantes Inmunológicos/uso terapéutico , Aterosclerosis/diagnóstico por imagen , Biomarcadores/análisis , Humanos , Inmunidad Humoral/efectos de los fármacos , Nanopartículas/uso terapéutico , Neoplasias/diagnóstico por imagen , Polisacáridos/uso terapéutico , Corona de Proteínas/inmunologíaRESUMEN
Nanodrug carrier will eventually enter the blood when intravenously injected or in other ways. Meanwhile, a series of toxic effects were caused to the body with the formation of nanoparticle protein corona. In our studies, we try to reveal the recognition mechanism of nanoparticle protein corona by monocyte and the damage effect on immune cells by activated complement of hydroxyapatite nanoparticles (HAP-NPs) and silicon dioxide nanoparticles (SiO2-NPs). So expressions of TLR4/CR1/CR were analyzed by flow cytometry (FCM) in order to illuminate the recognition mechanism of nanoparticle protein corona by monocyte. And the expression of ROS, cytokines, adhesion molecules, and arachidonic acid was measured when THP-1 and HUVECs were stimulated by NP-activated complement. The results showed that HAP-NPs can be recognized by the opsonin receptor (iC3b/CR3) model, while plasma protein, opsonin receptor, and Toll-like receptors are all likely launch cell recognition of SiO2-NPs. And it was considerate that NP-activated complement can damage THP-1 and HUVECs, including oxidative stress, inflammation, and increased vascular permeability. So the surface of nanodrug carrier can be modified to avoid being clear and reduce the efficacy according to the three receptors (TLR4/CR1/CR3).
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Durapatita/química , Células Endoteliales de la Vena Umbilical Humana/inmunología , Antígeno de Macrófago-1/inmunología , Monocitos/inmunología , Nanopartículas/química , Receptores de Complemento 3b/inmunología , Dióxido de Silicio/química , Activación de Complemento/inmunología , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Corona de Proteínas/inmunología , Células THP-1 , Receptor Toll-Like 4/inmunologíaRESUMEN
The significance of protein coronas on the biological fates of nanoparticles has been widely recognized. Therefore, the alterations on biological effects caused by protein coronas need systemic study and interpretation to design novel safe and efficient nanomedicines. In the present study, we present a comprehensive quantitative analysis of the protein coronas on gold nanorods modified with various surface ligands of different chemical compositions and charges. The design of surface ligands is of utmost importance for the functionalization of nanoparticles, and further, the ligand-induced biological identity determines the fate of nanoparticles in the human body. We found that the surface chemistry influences the composition of the protein corona more profoundly than surface charge. Since the first and most important challenge for administrated nanomedicines is navigating the interaction with macrophages, we further investigated how the surface chemistry-induced specific protein corona affects the phagocytosis and immune responses of macrophages exposed to the corona-nanoparticle complexes. Our results reveal that the protein corona alters the internalization pathways of gold nanorods by macrophages via the interactions of the predominant coronal proteins with specific receptors on the cell membrane. The cytokine secretion profile of macrophages is also highly dependent on the adsorption pattern of the protein corona. The more abundant proteins involved in immune responses, such as acute phase, complement, and tissue leakage proteins, present in the acquired nanoparticle corona, the more macrophage interleukin-1ß (IL-1ß) released is stimulated. The ligand-protein corona composition-immune response coefficient analysis may serve next-generation nanomedicines with high efficiency and good safety for better clinical translation.
Asunto(s)
Macrófagos/inmunología , Corona de Proteínas/química , Corona de Proteínas/inmunología , Endocitosis , Oro/química , Humanos , Nanotubos , Transducción de Señal , Propiedades de Superficie , Células THP-1RESUMEN
Nanoparticles are becoming an increasingly popular tool for biomedical imaging and drug delivery. While the prevalence of nanoparticle drug-delivery systems reported in the literature increases yearly, relatively little translation from the bench to the bedside has occurred. It is crucial for the scientific community to recognize this shortcoming and re-evaluate standard practices in the field, to increase clinical translatability. Currently, nanoparticle drug-delivery systems are designed to increase circulation, target disease states, enhance retention in diseased tissues, and provide targeted payload release. To manage these demands, the surface of the particle is often modified with a variety of chemical and biological moieties, including PEG, tumor targeting peptides, and environmentally responsive linkers. Regardless of the surface modifications, the nano-bio interface, which is mediated by opsonization and the protein corona, often remains problematic. While fabrication and assessment techniques for nanoparticles have seen continued advances, a thorough evaluation of the particle's interaction with the immune system has lagged behind, seemingly taking a backseat to particle characterization. This review explores current limitations in the evaluation of surface-modified nanoparticle biocompatibility and in vivo model selection, suggesting a promising standardized pathway to clinical translation.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/uso terapéutico , Corona de Proteínas/química , Proyectos de Investigación/tendencias , Investigación Biomédica Traslacional/métodos , Acromegalia/diagnóstico por imagen , Acromegalia/inmunología , Acromegalia/patología , Acromegalia/terapia , Anemia/diagnóstico por imagen , Anemia/inmunología , Anemia/patología , Anemia/terapia , Animales , Bibliometría , Diagnóstico por Imagen/métodos , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Nanopartículas/química , Nanopartículas/ultraestructura , Neoplasias/diagnóstico por imagen , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Polietilenglicoles/química , Corona de Proteínas/inmunología , Propiedades de SuperficieRESUMEN
Extensive exploitation of titanium dioxide nanoparticles (TiO2NPs) augments rapid release into the marine environment. When in contact with the body fluids of marine invertebrates, TiO2NPs undergo a transformation and adhere various organic molecules that shape a complex protein corona prior to contacting cells and tissues. To elucidate the potential extracellular signals that may be involved in the particle recognition by immune cells of the sea urchin Paracentrotus lividus, we investigated the behavior of TiO2NPs in contact with extracellular proteins in vitro. Our findings indicate that TiO2NPs are able to interact with sea urchin proteins in both cell-free and cell-conditioned media. The two-dimensional proteome analysis of the protein corona bound to TiO2NP revealed that negatively charged proteins bound preferentially to the particles. The main constituents shaping the sea urchin cell-conditioned TiO2NP protein corona were proteins involved in cellular adhesion (Pl-toposome, Pl-galectin-8, Pl-nectin) and cytoskeletal organization (actin and tubulin). Immune cells (phagocytes) aggregated TiO2NPs on the outer cell surface and within well-organized vesicles without eliciting harmful effects on the biological activities of the cells. Cells showed an active metabolism, no oxidative stress or caspase activation. These results provide a new level of understanding of the extracellular proteins involved in the immune-TiO2NP recognition and interaction in vitro, confirming that primary immune cell cultures from P. lividus can be an optional model for swift and efficient immune-toxicological investigations.
Asunto(s)
Nanopartículas/administración & dosificación , Corona de Proteínas/inmunología , Erizos de Mar/inmunología , Titanio/inmunología , Animales , Adhesión Celular/inmunología , Galectinas/inmunología , Glicoproteínas/inmunología , Nectinas/inmunología , Paracentrotus/inmunología , Fagocitos/inmunología , Proteoma/inmunologíaRESUMEN
Alzheimer's disease (AD) is a primary neurological disease with no effective cure. A hallmark of AD is the presence of intracellular tangles and extracellular plaques derived from the aberrant aggregation of tau- and beta-amyloid (Aß). Aß presents in the brain as well as in cerebrospinal fluid and the circulation, and Aß toxicity has been attributed to amyloidosis and inflammation, among other causes. In this study, the effects of the plasma protein corona have been investigated with regard to the blood cell association and cytokine secretion of oligomeric (Aßo) and fibrillar Aß1-42(Aßf), two major forms of the peptide aggregates. Aßo displayed little change in membrane association in whole blood or washed blood (i.e., cells in the absence of plasma proteins) at 37 °C, while Aßf showed a clear preference for binding with all cell types sans plasma proteins. Immune cells exposed to Aßo, but not to Aßf, resulted in significant expression of cytokines IL-6 and TNF measured in real-time by a localized surface plasmon resonance sensor. These observations indicate greater immune cell association and cytokine stimulation of Aßo than Aßf and shed new light on the contrasting toxicities of Aßo and Aßf resulting from their differential capacities in acquiring a plasma protein corona. These results further implicate a close connection between Aß amyloidosis and immunopathology in AD.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Amiloide/inmunología , Fragmentos de Péptidos/química , Placa Amiloide/inmunología , Corona de Proteínas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amiloide/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/inmunología , Encéfalo/inmunología , Encéfalo/patología , Citocinas/biosíntesis , Citocinas/química , Humanos , Microglía/inmunología , Neuronas/inmunología , Neuronas/patología , Fragmentos de Péptidos/inmunología , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/patología , Corona de Proteínas/inmunología , Transporte de Proteínas/inmunologíaRESUMEN
Enhanced understanding of bio-nano interaction requires recognition of hidden factors such as protein corona, a layer of adsorbed protein around nano-systems. This study compares the biological identity and fingerprint profile of adsorbed proteins on PLGA-based nanoparticles through nano-liquid chromatography-tandem mass spectrometry. The total proteins identified in the corona of nanoparticles (NPs) with different in size, charge and compositions were classified based on molecular mass, isoelectric point and protein function. A higher abundance of complement proteins was observed in modified NPs with an increased size, while NPs with a positive surface charge exhibited the minimum adsorption for immunoglobulin proteins. A correlation of dysopsonin/opsonin ratio was found with cellular uptake of NPs exposed to two positive and negative Fc receptor cell lines. Although the higher abundance of dysopsonins such as apolipoproteins may cover the active sites of opsonins causing a lower uptake, the correlation of adsorbed dysopsonin/opsonin proteins on the NPs surface has an opposite trend with the intensity of cell uptake. Despite the reduced uptake of corona-coated NPs in comparison with pristine NPs, the dysopsonin/opsonin ratio controlled by the physicochemistry properties of NPs could potentially be used to tune up the cellular delivery of polymeric NPs.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas/química , Proteínas Opsoninas , Corona de Proteínas , Animales , Células CHO , Cricetulus , Humanos , Ratones , Proteínas Opsoninas/química , Proteínas Opsoninas/inmunología , Tamaño de la Partícula , Corona de Proteínas/química , Corona de Proteínas/inmunología , Células RAW 264.7RESUMEN
Despite the progress of modern medicine, oncological diseases are still among the most common causes of death of adult populations in developed countries. The current therapeutic approaches are imperfect, and the high mortality of oncological patients under treatment, the lack of personalized strategies, and severe side effects arising as a result of treatment force seeking new approaches to therapy of malignant tumors. During the last decade, cancer immunotherapy, an approach that relies on activation of the host antitumor immune response, has been actively developing. Cancer immunotherapy is the most promising trend in contemporary fundamental and practical oncology, and restoration of the pathologically altered tumor microenvironment is one of its key tasks, in particular, the reprogramming of tumor macrophages from the immunosuppressive M2-phenotype into the proinflammatory M1-phenotype is pivotal for eliciting antitumor response. This review describes the current knowledge about macrophage classification, mechanisms of their polarization, their role in formation of the tumor microenvironment, and strategies for changing the functional activity of M2-macrophages, as well as problems of targeted delivery of immunostimulatory signals to tumor macrophages using nanoparticles.
Asunto(s)
Inmunoterapia , Macrófagos/metabolismo , Nanopartículas/metabolismo , Neoplasias/terapia , Animales , Polaridad Celular/fisiología , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Microscopía Intravital , Activación de Macrófagos/efectos de los fármacos , Macrófagos/química , Macrófagos/clasificación , Ratones , Nanopartículas/química , Fenotipo , Corona de Proteínas/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
In vivo liposomes, like other types of nanoparticles, acquire a totally new 'biological identity' due to the formation of a biomolecular coating known as the protein corona that depends on and modifies the liposomes' synthetic identity. The liposome-protein corona is a dynamic interface that regulates the interaction of liposomes with the physiological environment. Here we show that the biological identity of liposomes is clearly linked to their sequestration from peripheral blood mononuclear cells (PBMCs) of healthy donors that ultimately leads to removal from the bloodstream. Pre-coating liposomes with an artificial corona made of human plasma proteins drastically reduces capture by circulating leukocytes in whole blood and may be an effective strategy to enable prolonged circulation in vivo. We conclude with a critical assessment of the key concepts of liposome technology that need to be reviewed for its definitive clinical translation.
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Leucocitos Mononucleares/inmunología , Liposomas/sangre , Liposomas/inmunología , Corona de Proteínas/inmunología , Adsorción , Proteínas Sanguíneas/inmunología , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Citometría de Flujo , Humanos , Leucocitos/inmunología , Liposomas/metabolismo , Liposomas/ultraestructura , Microscopía Electrónica de Transmisión , Corona de Proteínas/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Células THP-1RESUMEN
Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid ß-peptide (Aß42), a major constituent of amyloid plaques in Alzheimer's disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.
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Péptidos beta-Amiloides/metabolismo , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno/inmunología , Fragmentos de Péptidos/metabolismo , Corona de Proteínas/inmunología , Virus Sincitial Respiratorio Humano/patogenicidad , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/virología , Animales , Líquido del Lavado Bronquioalveolar/virología , Línea Celular Tumoral , Chlorocebus aethiops , Modelos Animales de Enfermedad , Femenino , Voluntarios Sanos , Herpes Simple/sangre , Herpes Simple/inmunología , Herpes Simple/patología , Herpesvirus Humano 1/inmunología , Humanos , Masculino , Ratones , Ratones Transgénicos , Agregado de Proteínas/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/inmunología , Células VeroAsunto(s)
Anticuerpos/metabolismo , Nanopartículas/metabolismo , Polietilenglicoles/metabolismo , Corona de Proteínas/metabolismo , Animales , Anticuerpos/sangre , Anticuerpos/inmunología , Activación de Complemento , Humanos , Nanopartículas/química , Polietilenglicoles/química , Corona de Proteínas/inmunologíaRESUMEN
Multiple studies highlight the strong prevalence of anti-poly(ethylene glycol) (anti-PEG) antibodies in the general human population. As we develop therapeutic modalities using this polymer, it is increasingly relevant to assess the importance of anti-PEG antibodies on biological performances. Here, we show that the anti-PEG Immunoglobulin M (IgM) raised in mice following the injection of polymeric nanoparticles could have significant neutralizing effects on subsequent doses of PEGylated nanosystems in vivo. The circulation times of PEGylated nanoparticles and liposomes were strongly reduced in animals with circulating anti-PEG IgMs, irrespective of the PEG density or the surface properties of the system. In comparison, despite that anti-PEG IgMs could bind free methoxy-terminated PEG and PEGylated bovine serum albumin, the circulation kinetics of these systems remained unaltered in the presence of antibodies. The binding of IgMs to the PEGylated surface of nanoparticles alters the nature of the proteins adsorbed in the surrounding corona, notably due to the activation of the complement cascade. These changes are responsible for the observed differences in circulation times. In comparison, the PEG-BSA is unable to activate complement, even in the presence of anti-PEG IgMs. These results inform on how anti-PEG antibodies can affect the fate of PEGylated nanomaterials and highlight how the architecture of nanoparticles impacts the deposition of the protein corona.
Asunto(s)
Inmunoglobulina M/inmunología , Nanopartículas , Poliésteres , Polietilenglicoles , Corona de Proteínas/inmunología , Animales , Activación de Complemento , Inmunoglobulina M/sangre , Masculino , Ratones , Nanopartículas/química , Nanopartículas/metabolismo , Poliésteres/metabolismo , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Corona de Proteínas/metabolismoRESUMEN
The increasing number of biological applications for black phosphorus (BP) nanomaterials has precipitated considerable concern about their interactions with physiological systems. Here we demonstrate the adsorption of plasma protein onto BP nanomaterials and the subsequent immune perturbation effect on macrophages. Using liquid chromatography tandem mass spectrometry, 75.8% of the proteins bound to BP quantum dots were immune relevant proteins, while that percentage for BP nanosheet-corona complexes is 69.9%. In particular, the protein corona dramatically reshapes BP nanomaterial-corona complexes, influenced cellular uptake, activated the NF-κB pathway and even increased cytokine secretion by 2-4-fold. BP nanomaterials induce immunotoxicity and immune perturbation in macrophages in the presence of a plasma corona. These findings offer important insights into the development of safe and effective BP nanomaterial-based therapies.
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Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Nanoestructuras/toxicidad , Fósforo/toxicidad , Corona de Proteínas/inmunología , Adsorción , Proteínas Sanguíneas/metabolismo , Línea Celular , Células HEK293 , Humanos , Técnicas In Vitro , Inflamación/etiología , Macrófagos/metabolismo , Nanoestructuras/química , Corona de Proteínas/metabolismo , Puntos Cuánticos/química , Puntos Cuánticos/toxicidadRESUMEN
Airborne fungal pathogens, predominantly Aspergillus fumigatus, can cause severe respiratory tract diseases. Here we show that in environments, fungal spores can already be decorated with nanoparticles. Using representative controlled nanoparticle models, we demonstrate that various nanoparticles, but not microparticles, rapidly and stably associate with spores, without specific functionalization. Nanoparticle-spore complex formation was enhanced by small nanoparticle size rather than by material, charge, or "stealth" modifications and was concentration-dependently reduced by the formation of environmental or physiological biomolecule coronas. Assembly of nanoparticle-spore surface hybrid structures affected their pathobiology, including reduced sensitivity against defensins, uptake into phagocytes, lung cell toxicity, and TLR/cytokine-mediated inflammatory responses. Following infection of mice, nanoparticle-spore complexes were detectable in the lung and less efficiently eliminated by the pulmonary immune defense, thereby enhancing A. fumigatus infections in immunocompromised animals. Collectively, self-assembly of nanoparticle-fungal complexes affects their (patho)biological identity, which may impact human health and ecology.
Asunto(s)
Aspergillus fumigatus/inmunología , Citocinas/inmunología , Pulmón/inmunología , Nanopartículas , Aspergilosis Pulmonar/inmunología , Esporas Fúngicas/inmunología , Células A549 , Animales , Humanos , Pulmón/patología , Ratones , Corona de Proteínas/inmunología , Aspergilosis Pulmonar/patología , Células THP-1RESUMEN
BACKGROUND: Nanoparticle (NP)-based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen-presenting cells. Their cellular distribution and serum protein interaction ("protein corona") after systemic administration and their effect on the functional properties of NPs is poorly understood. OBJECTIVES: We analyzed the relevance of the protein corona on cell type-selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy. METHODS: The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxis and allergic asthma were assessed. RESULTS: DEX-NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG2a production. Treatment of OVA-sensitized mice with the DEX-NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition. CONCLUSIONS: Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses.
Asunto(s)
Anafilaxia/inmunología , Linfocitos B/inmunología , Hipersensibilidad/inmunología , Nanopartículas/administración & dosificación , Corona de Proteínas/inmunología , Animales , Antígenos/administración & dosificación , Dextranos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Femenino , Compuestos Ferrosos/administración & dosificación , Lectinas/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligodesoxirribonucleótidos/administración & dosificación , Ovalbúmina/administración & dosificación , Linfocitos T/inmunología , Vacunas/administración & dosificaciónRESUMEN
Studying the interactions of nanoparticles (NPs) with serum proteins is necessary for the rational development of nanocarriers. Optimum surface chemistry is a key consideration to modulate the formation of the serum protein corona (PC) and the resultant immune response. We investigated the constituent of the PC formed by hyaluronic acid-coated chitosan NPs (HA-CS NPs). Non-decorated chitosan NPs (CS NPs) and alginate-coated chitosan NPs (Alg-CS NPs) were utilized as controls. Results show that HA surface modifications significantly reduced protein adsorption relative to controls. Gene Ontology analysis demonstrates that HA-CS NPs were the least immunogenic nanocarriers. Indeed, less inflammatory proteins were adsorbed onto HA-CS NPs as opposed to CS and Alg-CS NPs. Interestingly, HA-CS NPs differentially adsorbed two unique anti-inflammatory proteins (ITIH4 and AGP), which were absent from the PC of both controls. On the other hand, CS and Alg-CS NPs selectively adsorbed a proinflammatory protein (Clusterin) that was not found on the surfaces of HA-CS NPs. While further studies are needed to investigate abilities of the PCs of only ITIH4 and AGP to modulate the interaction of NPs with the host immune system, our results suggest that this proof-of-concept could potentially be utilized to reduce the immunogenicity of a wide range of nanomaterials.