How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism

Immunemetabolism; Metabolism; NanoceriaInmunometabolismo; Metabolismo; NanoceriaImmunemetabolisme; Metabolisme; NanocèriaDysregulation of the immune system is associated with an overproduction of metabolic reactive oxygen species (ROS) and consequent oxidative stress. By buffering excess ROS, cerium oxide (CeO2) nanoparticles (NPs) (nanoceria) not only protect from oxidative stress consequence of inflammation but also modulate the immune response towards inflammation resolution. Immunomodulation is the modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and it is part of immunotherapy, in which immune responses are induced, amplified, attenuated, or prevented according to therapeutic goals. For decades, it has been observed that immune cells transform from relative metabolic quiescence to a highly active metabolic state during activation(1). These changes in metabolism affect fate and function over a broad range of timescales and cell types, always correlated to metabolic changes closely associated with mitochondria number and morphology. The question is how to control the immunochemical potential, thereby regulating the immune response, by administering cellular power supply. In this regard, immune cells show different general catabolic modes relative to their activation status, linked to their specific functions (maintenance, scavenging, defense, resolution, and repair) that can be correlated to different ROS requirements and production. Properly formulated, nanoceria is highly soluble, safe, and potentially biodegradable, and it may overcome current antioxidant substances limitations and thus open a new era for human health management

The development of highly dense highly protected surfactant ionizable lipid RNA loaded nanoparticles

Nanopartículas lipídicas ionizables; FarmacocinéticaIonizable lipid nanoparticles; PharmacokineticsNanopartícules lipídiques ionitzables; FarmacocinèticaThe long quest for efficient drug administration has been looking for a universal carrier that can precisely transport traditional drugs, new genomic and proteic therapeutic agents. Today, researchers have found conditions to overcome the two main drug delivery dilemmas. On the one side, the versatility of the vehicle to efficiently load, protect and transport the drug and then release it at the target place. On the other hand, the questions related to the degree of PEGylation which are needed to avoid nanoparticle (NP) aggregation and opsonization while preventing cellular uptake. The development of different kinds of lipidic drug delivery vehicles and particles has resulted in the development of ionizable lipid nanoparticles (iLNPs), which can overcome most of the typical drug delivery problems. Proof of their success is the late approval and massive administration as the prophylactic vaccine for SARS-CoV-2. These ILNPs are built by electrostatic aggregation of surfactants, the therapeutic agent, and lipids that self-segregate from an aqueous solution, forming nanoparticles stabilized with lipid polymers, such as PEG. These vehicles overcome previous limitations such as low loading and high toxicity, likely thanks to low charge at the working pH and reduced size, and their entry into the cells via endocytosis rather than membrane perforation or fusion, always associated with higher toxicity. We herein revise their primary features, synthetic methods to prepare and characterize them, pharmacokinetic (administration, distribution, metabolization and excretion) aspects, and biodistribution and fate. Owing to their advantages, iLNPs are potential drug delivery systems to improve the management of various diseases and widely available for clinical use.We acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I+D+i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya

Nucleation and growth of gold nanoparticles in the presence of different surfactants: a dissipative particle dynamics study

Colloids; Computational chemistry; NanoparticlesColoides; Química computacional; NanopartículasCol·loides; Química computacional; NanopartículesNanoparticles (NPs) show promising applications in biomedicine, catalysis, and energy harvesting. This applicability relies on controlling the material’s features at the nanometer scale. Surfactants, a unique class of surface-active molecules, have a remarkable ability to tune NPs activity; provide specific functions, avoid their aggregation, and create stable colloidal solutions. Surfactants also control nanoparticles’ nucleation and growth processes by modifying nuclei solubility and surface energy. While nucleation seems independent from the surfactant, NP’s growth depends on it. NP`s size is influenced by the type of functional group (C, O, S or N), length of its C chain and NP to surfactant ratio. In this paper, gold nanoparticles (Au NPs) are taken as model systems to study how nucleation and growth processes are affected by the choice of surfactants by Dissipative Particle Dynamics (DPD) simulations. DPD has been mainly used for studying biochemical structures, like lipid bilayer models. However, the study of solid NPs, and their conjugates, needs the introduction of a new metallic component. To represent the collective phenomena of these large systems, their degrees of freedom are reduced by Coarse-Grained (CG) models. DPD behaved as a powerful tool for studying complex systems and shedding some light on some experimental observations, otherwise difficult to explain.Authors are gratefully acknowledged for a fellowship to R.S-L provided by Universitat Autònoma de Barcelona, and for the financial support obtained through grant number RTI2018-099965-B-I00 from Ministerio de Ciencia, Innovación y Universidades, Spain. NGB and VP acknowledge financial support from R&D&I projects for international joint programming from MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and from Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya

The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

Inflamació; Immunitat innata; NanopartículesInflamación; Inmunidad innata; NanopartículasInflammation; Innate immunity; NanoparticlesThe immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.This research was funded by the EU Commission H2020 project PANDORA (GA 671881; to D.B., P.I. and V.P.). Additional funds were provided by the EU Commission H2020 project ENDONANO (GA 812661; to P.I. and D.B.), the Italian MIUR InterOmics Flagship projects MEMORAT and MAME (to D.B. and P.I.), the Italian MIUR/PRIN-20173ZECCM (to P.I.), the CAS President’s International Fellowship Programme (PIFI; award 2020VBA0028; to D.B.), Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER, UE), and Generalitat de Catalunya (2017-SGR-1431) (V.P.)

Hollow metal nanostructures for enhanced plasmonics: synthesis, local plasmonic properties and applications

Hollow nanostructures; Surface plasmon resonances (SPRs); Plasmon hybridizationNanoestructures buides; Ressonància de superfície de plasmó; Hibridació de plasmóNanoestructures vacías; Resonancia de superficie de plasmón; Hibridación de plasmónMetallic nanostructures have received great attention due to their ability to generate surface plasmon resonances, which are collective oscillations of conduction electrons of a material excited by an electromagnetic wave. Plasmonic metal nanostructures are able to localize and manipulate the light at the nanoscale and, therefore, are attractive building blocks for various emerging applications. In particular, hollow nanostructures are promising plasmonic materials as cavities are known to have better plasmonic properties than their solid counterparts thanks to the plasmon hybridization mechanism. The hybridization of the plasmons results in the enhancement of the plasmon fields along with more homogeneous distribution as well as the reduction of localized surface plasmon resonance (LSPR) quenching due to absorption. In this review, we summarize the efforts on the synthesis of hollow metal nanostructures with an emphasis on the galvanic replacement reaction. In the second part of this review, we discuss the advancements on the characterization of plasmonic properties of hollow nanostructures, covering the single nanoparticle experiments, nanoscale characterization via electron energy-loss spectroscopy and modeling and simulation studies. Examples of the applications, i.e. sensing, surface enhanced Raman spectroscopy, photothermal ablation therapy of cancer, drug delivery or catalysis among others, where hollow nanostructures perform better than their solid counterparts, are also evaluated

Hollow metal nanostructures for enhanced plasmonics: synthesis, local plasmonic properties and applications

Hollow nanostructures; Surface plasmon resonances (SPRs); Plasmon hybridizationNanoestructures buides; Ressonància de superfície de plasmó; Hibridació de plasmóNanoestructures vacías; Resonancia de superficie de plasmón; Hibridación de plasmónMetallic nanostructures have received great attention due to their ability to generate surface plasmon resonances, which are collective oscillations of conduction electrons of a material excited by an electromagnetic wave. Plasmonic metal nanostructures are able to localize and manipulate the light at the nanoscale and, therefore, are attractive building blocks for various emerging applications. In particular, hollow nanostructures are promising plasmonic materials as cavities are known to have better plasmonic properties than their solid counterparts thanks to the plasmon hybridization mechanism. The hybridization of the plasmons results in the enhancement of the plasmon fields along with more homogeneous distribution as well as the reduction of localized surface plasmon resonance (LSPR) quenching due to absorption. In this review, we summarize the efforts on the synthesis of hollow metal nanostructures with an emphasis on the galvanic replacement reaction. In the second part of this review, we discuss the advancements on the characterization of plasmonic properties of hollow nanostructures, covering the single nanoparticle experiments, nanoscale characterization via electron energy-loss spectroscopy and modeling and simulation studies. Examples of the applications, i.e. sensing, surface enhanced Raman spectroscopy, photothermal ablation therapy of cancer, drug delivery or catalysis among others, where hollow nanostructures perform better than their solid counterparts, are also evaluated

Recovering What Matters: High Protein Recovery after Endotoxin Removal from LPS-Contaminated Formulations Using Novel Anti-Lipid A Antibody Microparticle Conjugates

Bioconjugation; Polystyrene particles; Supramolecular structuresBioconjugación; Partículas de poliestireno; Estructuras supramolecularesBioconjugació; Partícules de poliestirè; Estructures supramolecularsEndotoxins or lipopolysaccharides (LPS), found in the outer membrane of Gram-negative bacterial cell walls, can stimulate the human innate immune system, leading to life-threatening symptoms. Therefore, regulatory limits for endotoxin content apply to injectable pharmaceuticals, and excess LPS must be removed before commercialization. The majority of available endotoxin removal systems are based on the non-specific adsorption of LPS to charged and/or hydrophobic surfaces. Albeit effective to remove endotoxins, the lack of specificity can result in the unwanted loss of essential proteins from the pharmaceutical formulation. In this work, we developed microparticles conjugated to anti-Lipid A antibodies for selective endotoxin removal. Anti-Lipid A particles were characterized using flow cytometry and microscopy techniques. These particles exhibited a depletion capacity > 6 ×103 endotoxin units/mg particles from water, as determined with two independent methods (Limulus Amebocyte Lysate test and nanoparticle tracking analysis). Additionally, we compared these particles with a non-specific endotoxin removal system in a series of formulations of increasing complexity: bovine serum albumin in water < insulin in buffer < birch pollen extracts. We demonstrated that the specific anti-Lipid A particles show a higher protein recovery without compromising their endotoxin removal capacity. Consequently, we believe that the specificity layer integrated by the anti-Lipid A antibody could be advantageous to enhance product yield.The project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 812661, H2020-MSCA-ITN-2018-812661 (ENDONANO)

Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease

Cerium oxide nanoparticles; Non-alcoholic fatty liver disease; Antioxidant agentNanopartículas de óxido de cerio; Enfermedad del hígado graso no alcohólico; Agente antioxidanteNanopartícules d’òxid de ceri; Malalties hepàtiques no alcohòliques; Agent antioxidantNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, ranging from steatosis to non-alcoholic steatohepatitis (NASH). Recently, cerium oxide nanoparticles (CeO2NPs) have emerged as a new antioxidant agent with hepatoprotective properties in experimental liver disease. The aim of the current investigation was to elucidate whether CeO2NPs display beneficial effects in an experimental model of NAFLD.Therefore, fifteen Wistar rats were subjected to a methionine and choline deficient diet (MCDD) for 6 weeks and intravenously treated with CeO2NP or vehicle during the weeks three and four of the diet. The effect of CeO2NPs on serum biochemistry, hepatic steatosis, inflammation, fatty acid content and expression of reactive oxygen species (ROS) and lipid metabolism related genes was assessed. MCDD fed rats showed increased inflammation, enhanced hepatic lipid accumulation of both saturated and unsaturated fatty acids (FAs) and overexpression of genes related to fatty liver and ROS metabolism. Treatment with CeO2NPs was able to reduce the size and content of hepatocyte lipid droplets, the hepatic concentration of triglyceride- and cholesterol ester-derived FAs and the expression of several genes involved in cytokine, adipokine and chemokine signaling pathways. These findings suggest that CeO2NPs could be of beneficial value in NAFLD.This research was supported by grants to W. Jiménez from Ministerio de Economia y Competitividad [grants SAF2015-64126R, 12-35979, BES-2013-063685, SAFRTI2018-094734-B-C21], to M. Morales-Ruiz [grant SAF2016-75358-R] and to G. Casals [grant P74844I/15/00777]; Cofinanced by FEDER, European Union, a way of making Europe, Agència de Gestió d’Ajuts Universitaris i de Recerca [grant SGR 2014/219]. The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III

Pharmacokinetics of PEGylated Gold Nanoparticles: In Vitro-In Vivo Correlation

Gold nanoparticles; Human cell lines; PharmacokineticsNanopartícules d'or; Línies cel·lulars humanes; FarmacocinèticaNanopartículas de oro; Líneas celulares humanas; FarmacocinéticaData suitable for assembling a physiologically-based pharmacokinetic (PBPK) model for nanoparticles (NPs) remain relatively scarce. Therefore, there is a trend in extrapolating the results of in vitro and in silico studies to in vivo nanoparticle hazard and risk assessment. To evaluate the reliability of such approach, a pharmacokinetic study was performed using the same polyethylene glycol-coated gold nanoparticles (PEG-AuNPs) in vitro and in vivo. As in vitro models, human cell lines TH1, A549, Hep G2, and 16HBE were employed. The in vivo PEG-AuNP biodistribution was assessed in rats. The internalization and exclusion of PEG-AuNPs in vitro were modeled as first-order rate processes with the partition coefficient describing the equilibrium distribution. The pharmacokinetic parameters were obtained by fitting the model to the in vitro data and subsequently used for PBPK simulation in vivo. Notable differences were observed in the internalized amount of Au in individual cell lines compared to the corresponding tissues in vivo, with the highest found for renal TH1 cells and kidneys. The main reason for these discrepancies is the absence of natural barriers in the in vitro conditions. Therefore, caution should be exercised when extrapolating in vitro data to predict the in vivo NP burden and response to exposure.This research was funded by the European Commission under the Horizon 2020 programme (HISENTS, Grant Agreement No. 685817 and VISION, Grant Agreement No. 857381). Financial support from the Structural Funds of EU by implementation of the project “Strategic research in SMART monitoring, treatment, and prevention against coronavirus (SARS-CoV-2)”, ITMS 2014+ code NFP313011ASS8 co-financed by the European Regional Development Fund

Metal transfer to sediments, invertebrates and fish following waterborne exposure to silver nitrate or silver sulfide nanoparticles in an indoor stream mesocosm

Engineered nanomaterials; Silver uptake; TroutNanomaterials dissenyats; Captació de plata; TruitaNanomateriales de ingeniería; Absorción de plata; TruchaThe fate of engineered nanomaterials in ecosystems is unclear. An aquatic stream mesocosm explored the fate and bioaccumulation of silver sulfide nanoparticles (Ag2S NPs) compared to silver nitrate (AgNO3). The aims were to determine the total Ag in water, sediment and biota, and to evaluate the bioavailable fractions of silver in the sediment using a serial extraction method. The total Ag in the water column from a nominal daily dose of 10 μg L−1 of Ag for the AgNO3 or Ag2S NP treatments reached a plateau of around 13 and 12 μg L−1, respectively, by the end of the study. Similarly, the sediment of both Ag-treatments reached ~380 μg Ag kg−1, and with most of it being acid-extractable/labile. The biota accumulated 4–59 μg Ag g−1 dw, depending on the type of Ag-treatment and organism. The oligochaete worm, Lumbriculus variegatus, accumulated Ag from the Ag2S exposure over time, which was similar to the AgNO3 treatment by the end of the experiment. The planarian, Girardia tigrina, and the chironomid larva, Chironomus riparius, showed much higher Ag concentrations than the oligochaete worms; and with a clearer time-dependent statistically significant Ag accumulation relative to the untreated controls. For the pulmonate snail, Physa acuta, bioaccumulation of Ag from AgNO3 and Ag2S NP exposures was observed, but was lower from the nano treatment. The AgNO3 exposure caused appreciable Ag accumulation in the water flea, Daphnia magna, but accumulation was higher in the Ag2S NP treatment (reaching 59 μg g−1 dw). In the rainbow trout, Oncorhynchus mykiss, AgNO3, but not Ag2S NPs, caused total Ag concentrations to increase in the tissues. Overall, the study showed transfer of total Ag from the water column to the sediment, and Ag bioaccumulation in the biota, with Ag from Ag2S NP exposure generally being less bioavailable than that from AgNO3.This work was supported by the project NanoFASE (Nanomaterial Fate and Speciation in the Environment), financed by the European Union's Horizon 2020 research and innovation programme under grant agreement no 646002. RDH was partly supported by NanoHarmony under grant agreement 885931 in Horizon 2020 while redrafting the main text. PVS was awarded with a PhD grant (SFRH/BD/51571/2014) by FCT – Fundação para a Ciência e a Tecnologia. SL and PVS received additional financial support from FCT/MCTES, through national funds, to CESAM (UIDP/50017/2020+UIDB/50017/2020+ LA/P/0094/2020)