Plasma Protein Corona Research Articles

Influence of chirality on protein corona formation of low-fouling chiral poly(2-oxazoline) coated nanoparticles

Low-fouling polymers play a crucial role in the development of therapeutic nanoparticles (NPs), which are commonly described as nanomedicines. These hydrophilic polymers are typically designed to favourably alter the protein corona that forms around a NP by reducing the binding of opsonins, resulting in reduced immune recognition and clearance. The polymer specific proteome of the corona is mainly dictated by the physicochemical properties of the polymer and several parameters such as hydrophilicity and charge have been explored to regulate its composition. To date, there has been little attention given to the influence of the chirality of the hydrophilic polymer on the composition of the corona. Water-soluble poly(2,4-dialkyl-2-oxazoline)s (PdOx) are a unique synthetic polymer class to explore the effect of chirality as they can be rendered optically active if enantiopure monomers are used for their synthesis. Herein we prepared two water-soluble poly(2,4-dimethyl-2-oxazoline)s (PdMeOx) of different handedness, alongside racemic PdMeOx and the well-established low-fouling structural isomer poly(2-ethyl-2-oxazoline) (PEtOx). All polymers were equipped with sulphur-containing xanthate moieties with high end-group fidelity, which enabled anchoring to gold nanoparticles (AuNPs) as a useful handle for evaluation of the polymer-specific fouling. It was revealed that a hard corona formed after exposing the coated AuNP to human plasma proteins as investigated by dynamic light scattering, SDS-PAGE and PierceTM bicinchoninic acid protein assay (BCA) revealing a similar protein adsorption between PEtOx and all three PdMeOx. Moreover, a detailed proteomics study using liquid chromatography coupled to mass spectrometry (LC–MS/MS) was performed and analysed by label-free quantitation (LFQ). Overall, the PdMeOx systems showed similar human plasma protein corona profiles compared to the PEtOx control. However, between the R- and S-PdMeOx enantiomers differences in protein population abundances were observed, suggesting the propensity for specific interaction of chiral PdOx with different elements of the proteome. Overall, the present study introduces PdMeOx as a chiral, low fouling polymer system, which can reduce protein fouling in a similar magnitude to the PEtOx control. Importantly, we provide a first insight into how changes in the chirality of PdMeOx can influence the components of the protein corona, which will inform the future design of PdOx nanotherapeutics.

Unraveling the impact of different liposomal formulations on the plasma protein corona composition might give hints on the targeting capability of nanoparticles.

Nanoparticles (NPs) interact with biological fluids after being injected into the bloodstream. The interactions between NPs and plasma proteins at the nano-bio interface affect their biopharmaceutical properties and distribution in the organ and tissues due to protein corona (PrC) composition, and in turn, modification of the resulting targeting capability. Moreover, lipid and polymer NPs, at their interface, affect the composition of PrC and the relative adsorption and abundance of specific proteins. To investigate this latter aspect, we synthesized and characterized different liposomal formulations (LFs) with lipids and polymer-conjugated lipids at different molar ratios, having different sizes, size distributions and surface charges. The PrC composition of various designed LFs was evaluated ex vivo in human plasma by label-free quantitative proteomics. We also correlated the relative abundance of identified specific proteins in the coronas of the different LFs with their physicochemical properties (size, PDI, zeta potential). The evaluation of outputs from different bioinformatic tools discovered protein clusters allowing to highlight: (i) common as well as the unique species for the various formulations; (ii) correlation between each identified PrC and the physicochemical properties of LFs; (iii) some preferential binding determined by physicochemical properties of LFs; (iv) occurrence of formulation-specific protein patterns in PrC. Investigating specific clusters in PrC will help decode the multivalent roles of the protein pattern components in the drug delivery process, taking advantage of the bio-nanoscale recognition and identification for significant advances in nanomedicine.

Uptake of extracellular vesicles into immune cells is enhanced by the protein corona.

The influence of a protein corona on the uptake of nanoparticles in cells has been demonstrated in various publications over the last years. Extracellular vesicles (EVs), can be seen as natural nanoparticles. However, EVs are produced under different cell culture conditions and little is known about the protein corona forming on EVs and its influence on their uptake by target cells. Here, we use a proteomic approach in order to analyze the protein composition of the EVs themselves and the protein composition of a human blood plasma protein corona around EVs. Moreover, we analyze the influence of the protein corona on EV uptake into human monocytes and compare it with the influence on the uptake of engineered liposomes. We show that the presence of a protein corona increases the uptake of EVs in human monocytes. While for liposomes this seems to be triggered by the presence of immunoglobulins in the protein corona, for EVs blocking the Fc receptors on monocytes did not show an influence of uptake. Therefore, other mechanisms of docking to the cell membrane and uptake are most like involved, demonstrating a clear difference between EVs and liposomes as technically produced nanocarriers.

Effect of initial particle size and surface charge on the formation of the plasma protein corona on chitosan‐based nanoparticles

AbstractWhen a nanoparticle interacts with the biological environment, its surface is covered by a layer of biomolecules such as proteins and lipids called a protein corona. Given the importance and impact of the protein corona on the fate of nanoparticles in the body, it is important to study the interaction of nanoparticles with proteins. This study investigated the impact of the initial size and surface charge of nanoparticles on the changes in protein corona thickness on chitosan‐based nanoparticles after exposure to blood plasma. To be able to separate the chitosan‐based nanoparticles from the blood plasma, magnetic nanoparticles were coated with chitosan (with a positive charge) and carboxymethyl chitosan (CMC; with a negative charge) in two different size ranges of 200–250 and 300–350 nm. The coated nanoparticles' chemical composition, properties, and morphology were investigated using Fourier‐transform infrared spectroscopy, X‐ray diffraction, dynamic light scattering (DLS), zeta potential measurements, transmission electron microscopy, and field emission scanning electron microscope. The results confirmed the formation of nanoparticles based on chitosan and CMC. Subsequently, these nanoparticles were exposed to blood plasma to examine the protein corona that formed. The DLS and zeta potential measurements showed that the surface charge and particle size of the nanoparticles significantly influenced the formation of the protein corona. The results revealed that the smaller particle size and the positive surface charge of the nanoparticles resulted in the formation of a thicker corona. In addition, it showed that after exposure to the blood plasma proteins, the positive charge of the particles changed to a negative charge.

Serum protein coating enhances the antisepsis efficacy of silver nanoparticles against multidrug-resistant Escherichia coli infections in mice.

Antimicrobial resistance poses a significant threat to public health and social development worldwide. This study aimed to investigate the effectiveness of silver nanoparticles (AgNPs) in treating multidrug-resistant bacterial infections. Eco-friendly spherical AgNPs were synthesized using rutin at room temperature. The biocompatibility of both polyvinyl pyrrolidone (PVP) and mouse serum (MS)-stabilized AgNPs was evaluated at 20 μg/mL and showed a similar distribution in mice. However, only MS-AgNPs significantly protected mice from sepsis caused by the multidrug-resistant Escherichia coli (E. coli) CQ10 strain (p = 0.039). The data revealed that MS-AgNPs facilitated the elimination of Escherichia coli (E. coli) in the blood and the spleen, and the mice experienced only a mild inflammatory response, as interleukin-6, tumor necrosis factor-α, chemokine KC, and C-reactive protein levels were significantly lower than those in the control group. The results suggest that the plasma protein corona strengthens the antibacterial effect of AgNPs in vivo and may be a potential strategy for combating antimicrobial resistance.

Synthesis of magnetic NaY zeolite for plasma proteomics application

Magnetically modified NaY zeolite has shown advantages in high-throughput and large-scale clinical plasma proteomic studies. In this study, magnetic NaY zeolite was prepared via an improved method, "layer by layer adhesion", using epoxy adhesive. The morphology, structure, and magnetic properties of magnetic NaY zeolite were characterized and tested by scanning electron microscope (SEM), fourier transform infrared spectrometer (FT-IR), X-ray diffractometer (XRD), and vibrating sample magnetometer (VSM), and using sodium dodecyl sulfonate-polyacrylamide gelelectrophoresis (SDS-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS) for plasma proteomics studies. The results showed that NaY zeolite was coated on the surface of Fe3O4 by epoxy adhesive, and such coating did not affect the surface properties of the magnetic zeolite. The saturation magnetization of magnetic NaY zeolite was measured as 9.964 emu g−1. Approximately 2929 proteins could be identified from plasma protein corona formed on magnetic NaY zeolite, reaching 97.6 % of the identification number of pure NaY zeolite. Furthermore, compared with NaY zeolite, the solid-liquid separation processes of magnetic zeolite during plasma proteomics studies were significantly reduced from half an hour to few minutes. Due to excellent plasma protein adsorption performance and rapid magnetic separation property, magnetic NaY zeolite is expected to become a powerful tool for the large-scale adsorption of low-abundant plasma proteins and high-throughput proteomic studies.

Comprehensive and deep profiling of the plasma proteome with protein corona on zeolite NaY

Proteomic characterization of plasma is critical for the development of novel pharmacodynamic biomarkers. However, the vast dynamic range renders the profiling of proteomes extremely challenging. Here, we synthesized zeolite NaY and developed a simple and rapid method to achieve comprehensive and deep profiling of the plasma proteome using the plasma protein corona formed on zeolite NaY. Specifically, zeolite NaY and plasma were co-incubated to form plasma protein corona on zeolite NaY (NaY-PPC), followed by conventional protein identification using liquid chromatography-tandem mass spectrometry. NaY was able to significantly enhance the detection of low-abundance plasma proteins, minimizing the “masking” effect caused by high-abundance proteins. The relative abundance of middle- and low-abundance proteins increased substantially from 2.54% to 54.41%, and the top 20 high-abundance proteins decreased from 83.63% to 25.77%. Notably, our method can quantify approximately 4000 plasma proteins with sensitivity up to pg/mL, compared to only about 600 proteins identified from untreated plasma samples. A pilot study based on plasma samples from 30 lung adenocarcinoma patients and 15 healthy subjects demonstrated that our method could successfully distinguish between healthy and disease states. In summary, this work provides an advantageous tool for the exploration of plasma proteomics and its translational applications.

Unraveling the Plasma Protein Corona by Ultrasonic Cavitation Augments Active-Transporting of Liposome in Solid Tumor.

Ligand/receptor-mediated targeted drug delivery has been widely recognized as a promising strategy for improving the clinical efficacy ofnanomedicines but is attenuated by the binding of plasma protein on the surface of nanoparticles to form a protein corona. Here, it is shown that ultrasonic cavitation can be used to unravel surface plasma coronas on liposomal nanoparticles through ultrasound (US)-induced liposomal reassembly. To demonstrate the feasibility and effectiveness of the method, transcytosis-targeting-peptide-decorated reconfigurable liposomes (LPGLs) loaded with gemcitabine (GEM) and perfluoropentane (PFP) are developed for cancer-targeted therapy. In the blood circulation, the targeting peptides are deactivated by the plasma corona and lose their targeting capability. Once they reach tumor blood vessels, US irradiation induces transformation of the LPGLs from nanodrops into microbubbles via liquid-gas phase transition and decorticate the surface corona by reassembly of the lipid membrane. The activated liposomes regain the capability to recognize the receptors on tumor neovascularization, initiate ligand/receptor-mediated transcytosis, achieve efficient tumor accumulation and penetration, and lead to potent antitumor activity in multiple tumor models of patient-derived tumor xenografts. This study presents an effective strategy to tackle the fluid biological barriers of the protein corona and develop transcytosis-targeting liposomes for active tumor transport and efficient cancer therapy.

The mechanism of Hepatocyte-Targeting and safety profile of Phospholipid-Free small unilamellar vesicles

Phospholipid-free small unilamellar vesicles (PFSUVs) composed of cholesterol and TWEEN80 (5:1 mol ratio), with an average diameter of 60 nm, displayed targeted delivery to the hepatocytes after intravenous (i.v.) injection. Here, we conducted a series of experiments to elucidate the hepatocyte targeting mechanism. The uptake of PFSUVs by HepG2 cells was increased by 3-fold in the presence of serum. The plasma protein corona adsorbed to PFSUVs was analyzed and subtypes of apolipoproteins were found enriched, specifically apolipoprotein AII (ApoA2). The cellular uptake was increased by 1.5-fold when the culture medium was supplemented with ApoA2, but not ApoC1 and ApoE. Furthermore, the cellular uptake of PFSUVs increased with increasing concentrations of ApoA2 in the medium and was almost completely blocked in the presence of BLT-1, an inhibitor for the scavenger receptor B-1 (SR-B1), which is a receptor for ApoA2. The data suggest that upon i.v. delivery, PFSUVs adsorbed plasma ApoA2 to the surface, which was recognized by SR-B1 expressed by the hepatocytes and then internalized. After internalization, mainly through the clathrin-mediated endocytosis, PFSUVs were found in the endosomes after 1–2 h post treatment and then lysosomes in 4 h. We also examined the cytotoxicity, hemolytic toxicity and complement activation of PFSUVs by incubating the formulation with HepG2 cells, red blood cells and human plasma, respectively, demonstrating no toxicity at concentrations higher than the therapeutic doses.

Plasma protein corona forming upon fullerene nanocomplex: Impact on both counterparts

Protein corona refers to the structure composed of biomolecules adsorbed on the surface of nanomaterials. The study on the effect of the interaction between protein and nanoparticles can provide an important guide for the application of nanodrug delivery. To provide a reference for the research on fullerene (C60) nanocomplex drug delivery systems, this work studied the interaction between C60 nanocomplex and a variety of plasma proteins. Research showed that the protein binding with C60 nanocomplex did not change the charge properties of protein. The proteins induced the aggregation of C60 nanocomplex. The circular dichroism spectra showed that the secondary structure of the proteins changed after binding to C60 nanocomplex. The ultraviolet–visible spectra showed that the effect of C60 nanocomplex on proteins was concentration-dependent. The fluorescence spectra showed that C60 nanocomplex could intrinsic fluorescence alteration of proteins. The adsorption capacity of C60 nanocomplex to proteins was changed at 0 h and 4 h. The interaction between nanocomplex and proteins might affect the morphological characteristics of nanocomplex and the conformation of proteins. This work could provide a reference for the research and development of C60 nanocomplex and other carbon-based nanocomplex as nanoparticulate drug delivery systems.

A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation.

Nanoparticles can acquire a plasma protein corona defining their biological identity. Corona functions were previously considered for cell‐derived extracellular vesicles (EVs). Here we demonstrate that nano‐sized EVs from therapy‐grade human placental‐expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell‐secreted soluble factors via tangential flow‐filtration (TFF) and subtractive tandem mass‐tag (TMT) proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein‐based flow cytometry, super‐resolution and electron microscopy verified EV identity. PLX‐EVs partly protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signalling in immune cells, and dose‐dependently inhibited T cell proliferation in vitro. Corona removal by size‐exclusion or ultracentrifugation abrogated angiogenesis. Re‐establishing an artificial corona by cloaking EVs with fluorescent albumin as a model protein or defined proangiogenic factors was depicted by super‐resolution microscopy, electron microscopy and zeta‐potential shift, and served as a proof‐of‐concept. Understanding EV corona formation will improve rational EV‐inspired nano‐therapy design.

The Effect of Surface Modification of PLGA Drug Carriers on Vascular Wall Adhesion and Plasma Protein Corona for Improved Vascular Targeting

The Effect of Surface Modification of PLGA Drug Carriers on Vascular Wall Adhesion and Plasma Protein Corona for Improved Vascular Targeting

Plasma proteins facilitates placental transfer of polystyrene particles

BackgroundNanoparticles, which are exposed to biological fluids are rapidly interacting with proteins and other biomolecules forming a corona. In addition to dimension, charge and material the distinct protein corona influences the interplay of nanoparticles with tissue barriers. In this study we were focused on the impact of in situ formed human plasma protein corona on the transfer of 80 nm polystyrene nanoparticles (PS-particles) across the human placenta. To study materno-to fetal PS transfer we used the human ex vivo placental perfusion approach, which represents an intact and physiological tissue barrier. To analyze the protein corona of PS particles we performed shotgun proteomics of isolated nanoparticles before and after tissue exposure.ResultsHuman plasma incubated with PS-particles of 80 nm and subsequent formed protein corona enhanced the transfer across the human placenta compared to PS-corona formed by bovine serum albumin and dextran which served as a control. Quantitative and qualitative changes of plasma proteins determined the changes in PS transfer across the barrier. Based on the analysis of the PS-proteome two candidate proteins, namely human albumin and immunoglobulin G were tested if these proteins may account for the enhanced PS-transfer across the placenta. Interestingly, the protein corona formed by human albumin significantly induced the transfer of PS-particles across the tissue compared to the formed IgG-corona.ConclusionIn total we demonstrate the PS corona dynamically and significantly evolves upon crossing the human placenta. Thus, the initial composition of PS particles in the maternal circulation is not predictive for their transfer characteristics and performance once beyond the barrier of the placenta. The precise mechanism of these effects remains to be elucidated but highlights the importance of using well designed biological models when testing nanoparticles for biomedical applications.

Targeting Tumorigenicity of Breast Cancer Stem Cells Using SAHA/Wnt-b Catenin Antagonist Loaded Onto Protein Corona of Gold Nanoparticles.

BackgroundAmong various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.Materials and MethodsWe prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.ResultsWe found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.ConclusionOur study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.

Human Plasma Protein Corona of Aβ Amyloid and Its Impact on Islet Amyloid Polypeptide Cross-Seeding.

Alzheimer's disease (AD) is the most severe form of neurological disorder, characterized by the presence of extracellular amyloid-β (Aβ) plaques and intracellular tau tangles. For decades, therapeutic strategies against the pathological symptoms of AD have often relied on the delivery of monoclonal antibodies to target specifically Aβ amyloid or oligomers, largely to no avail. Aβ can be traced in the brain as well as in cerebrospinal fluid and the circulation, giving rise to abundant opportunities to interact with their environmental proteins. Using liquid chromatography tandem-mass spectrometry, here we identified for the first time the protein coronae of the two major amyloid forms of Aβ-Aβ1-42 and Aβ1-40-exposed to human blood plasma. Out of the proteins identified in all groups, 58 proteins were unique to the Aβ1-42 samples and 31 proteins unique to the Aβ1-40 samples. Both fibrillar coronae consisted of proteins significant in complement activation, inflammation, and protein metabolic pathways involved in the pathology of AD. Structure-wise, the coronal proteins often possessed multidomains of high flexibility to maximize their association with the amyloid fibrils. The protein corona hindered recognition of Aβ1-42 fibrils by their structurally specific antibodies and accelerated the aggregation but not the β-cell toxicity of human islet amyloid polypeptide, the peptide associated with type 2 diabetes. This study highlights the importance of understanding the structural, functional, and pathological implications of the amyloid protein corona for the development of therapeutics against AD and a range of amyloid diseases.

Differential Roles of Plasma Protein Corona on Immune Cell Association and Cytokine Secretion of Oligomeric and Fibrillar Beta-Amyloid.

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 (Aβ). Aβ presents in the brain as well as in cerebrospinal fluid and the circulation, and Aβ 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 (Aβo) and fibrillar Aβ1-42(Aβf), two major forms of the peptide aggregates. Aβo 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 Aβf showed a clear preference for binding with all cell types sans plasma proteins. Immune cells exposed to Aβo, but not to Aβf, 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 Aβo than Aβf and shed new light on the contrasting toxicities of Aβo and Aβf resulting from their differential capacities in acquiring a plasma protein corona. These results further implicate a close connection between Aβ amyloidosis and immunopathology in AD.

Influence of dynamic flow conditions on adsorbed plasma protein corona and surface-induced thrombus generation on antifouling brushes

The information regarding the nature of protein corona (and its changes) and cell binding on biomaterial surface under dynamic conditions is critical to dissect the mechanism of surface-induced thrombosis. In this manuscript, we investigated the nature of protein corona and blood cell binding in heparinized recalcified human plasma, platelet rich plasma and whole blood on three highly hydrophilic antifouling polymer brushes, (poly(N, N-dimethylacrylamide) (PDMA), poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and poly[N-(2-hydroxypropyl) methacrylamide] (PHPMA) using an in vitro blood loop model at comparable arterial and venous flow, and static conditions. A fluid dynamics model was used initially to better understand the resulting flow patterns in a vertical channel containing the substrates to arrive at the placement of the substrates within the blood loop. The protein binding on the brush modified substrates was determined using ellipsometry, fluorescence microscopy and the nature of the protein corona was investigated using mass spectrometry based proteomics. The flow elevated fouling on brush coated surface from blood. The extent of plasma protein adsorption and platelet adhesion onto PDMA brush was lower than other surfaces in both static and flow conditions. The profiles of adsorbed protein corona showed strong dependence on the test conditions (static vs. flow), and the chemistry of the polymer brushes. Specially, the PDMA brush under flow conditions was more enriched with coagulation proteins, complement proteins, vitronectin and fibronectin but was less enriched with serum albumin. Apolipoprotein B-100 and complement proteins were the most abundant proteins seen on PMPC and PHPMA surfaces under both flow and static conditions, respectively. Unlike PDMA brush, the flow conditions did not affect the composition of protein corona on PMPC and PHPMA brushes. The nature of the protein corona formed in flow conditions influenced the platelet and red blood cell binding. The dependence of shear stress on platelet adhesion from platelet rich plasma and whole blood highlights the contribution of red blood cells in enhancing platelet adhesion on the surface under high shear condition.

ZnO Interactions with Biomatrices: Effect of Particle Size on ZnO-Protein Corona.

Zinc oxide (ZnO) nanoparticles (NPs) have been widely used for food fortification, because zinc is essential for many enzyme and hormone activities and cellular functions, but public concern about their potential toxicity is increasing. Interactions between ZnO and biomatrices might affect the oral absorption, distribution, and toxicity of ZnO, which may be influenced by particle size. In this study, ZnO interactions with biomatrices were investigated by examining the physicochemical properties, solubility, protein fluorescence quenching, particle–protein corona, and intestinal transport with respect to the particle size (bulk vs. nano) in simulated gastrointestinal (GI) and plasma fluids and in rat-extracted fluids. The results demonstrate that the hydrodynamic radii and zeta potentials of bulk ZnO and nano ZnO in biofluids changed in different ways, and that nano ZnO induced higher protein fluorescence quenching than bulk ZnO. However, ZnO solubility and its intestinal transport mechanism were unaffected by particle size. Proteomic analysis revealed that albumin, fibrinogen, and fibronectin play roles in particle–plasma protein corona, regardless of particle size. Furthermore, nano ZnO was found to interact more strongly with plasma proteins. These observations show that bulk ZnO and nano ZnO interact with biomatrices in different ways and highlight the need for further study of their long-term toxicity.

Plasma Protein Adsorption and Biological Identity of Systemically Administered Nanoparticles

Although a variety of nanoparticles (NPs) have been used for drug delivery applications, their surfaces are immediately covered by plasma protein corona upon systemic administration. As a result, the adsorbed proteins create a unique biological identity of the NPs that lead to unpredictable performance. The protein corona on NPs could also impede active targeting, induce off-target effects, trigger particle clearance and even provoke toxicity. This article reviews the fundamentals of NP-plasma protein interaction, the consequences of the interactions, and provides insights into the correlations of protein corona with biodistribution and cellular delivery. We hope that this review will trigger additional questions and possible solutions that lead to more favorable developments in NP-based targeted delivery systems.

IgA and IgM protein primarily drive plasma corona-induced adhesion reduction of PLGA nanoparticles in human blood flow.

The high abundance of immunoglobulins (Igs) in the plasma protein corona on poly(lactic‐co‐glycolic) acid (PLGA)‐based vascular‐targeted carriers (VTCs) has previously been shown to reduce their adhesion to activated endothelial cells (aECs) in human blood flow. However, the relative role of individual Ig classes (e.g., IgG, IgA, and IgM) in causing adhesion reduction remains largely unknown. Here, we characterized the influence of specific Ig classes in prescribing the binding efficiency of PLGA nano‐sized VTCs in blood flow. Specifically, we evaluated the flow adhesion to aECs of PLGA VTCs with systematic depletion of various Igs in their corona. Adhesion reduction was largely eliminated for PLGA VTCs when all Igs were removed from the corona. Furthermore, re‐addition of IgA or IgM to the Igs‐depleted corona reinstated the low adhesion of PLGA VTCs, as evidenced by ∼40–70% reduction relative to particles with an Igs‐deficient corona. However, re‐addition of a high concentration of IgG to the Igs‐depleted corona did not cause significant adhesion reduction. Overall, the presented results reveal that PLGA VTC adhesion reduction in blood flows is primarily driven by high adsorption of IgA and IgM in the particle corona. Pre‐coating of albumin on PLGA VTCs mitigated the extent of adhesion reduction in plasma for some donors but was largely ineffective in general. Overall, this work may shed light into effective control of protein corona composition, thereby enhancing VTC functionality in vivo for eventual clinical use.