The biomolecule corona of lipid nanoparticles contains circulating cell-free DNA

Gardner, Lois; Warrington, Jessica; Rogan, Jane; Rothwell, Dominic G.; Brady, Ged; Dive, Caroline; Kostarelos, Kostas; Hadjidemetriou, Marilena

doi:10.1039/d0nh00333f

Cited by 21 publications

(22 citation statements)

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“…The physicochemical characteristics of the liposomes employed are summarized in Figure e. Corona-coated liposomes were purified from any unbound plasma components by a two-step purification protocol which is based on size exclusion chromatography followed by membrane ultrafiltration, as previously extensively optimized and described. ,,,,− This protocol has been previously shown to completely eliminate unbound proteins and to result in a reproducible composition of protein corona . The resultant purified in vivo protein coronas at the three different time points were comprehensively characterized and compared (Figure f).…”

Section: Resultsmentioning

confidence: 99%

Nanoparticle-Enabled Enrichment of Longitudinal Blood Proteomic Fingerprints in Alzheimer’s Disease

et al. 2021

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Blood-circulating biomarkers have the potential to detect Alzheimer's disease (AD) pathology before clinical symptoms emerge and to improve the outcomes of clinical trials for disease-modifying therapies. Despite recent advances in understanding concomitant systemic abnormalities, there are currently no validated or clinically used blood-based biomarkers for AD. The extremely low concentration of neurodegeneration-associated proteins in blood necessitates the development of analytical platforms to address the "signal-to-noise" issue and to allow an in-depth analysis of the plasma proteome. Here, we aimed to discover and longitudinally track alterations of the blood proteome in a transgenic mouse model of AD, using a nanoparticle-based proteomics enrichment approach. We employed blood-circulating, lipid-based nanoparticles to extract, analyze and monitor AD-specific protein signatures and to systemically uncover molecular pathways associated with AD progression. Our data revealed the existence of multiple proteomic signals in blood, indicative of the asymptomatic stages of AD. Comprehensive analysis of the nanoparticle-recovered blood proteome by label-free liquid chromatography−tandem mass spectrometry resulted in the discovery of AD-monitoring signatures that could discriminate the asymptomatic phase from amyloidopathy and cognitive deterioration. While the majority of differentially abundant plasma proteins were found to be upregulated at the initial asymptomatic stages, the abundance of these molecules was significantly reduced as a result of amyloidosis, suggesting a disease-stage-dependent fluctuation of the AD-specific blood proteome. The potential use of the proposed nano-omics approach to uncover information in the blood that is directly associated with brain neurodegeneration was further exemplified by the recovery of focal adhesion cascade proteins. We herein propose the integration of nanotechnology with already existing proteomic analytical tools in order to enrich the identification of blood-circulating signals of neurodegeneration, reinvigorating the potential clinical utility of the blood proteome at predicting the onset and kinetics of the AD progression trajectory.

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Section: Resultsmentioning

confidence: 99%

Nanoparticle-Enabled Enrichment of Longitudinal Blood Proteomic Fingerprints in Alzheimer’s Disease

et al. 2021

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“…The elevations of a protein, lipid, and nucleic acid in the PEG-GNP deposited regions are supposed to associate with biomolecule adsorption, immune response, alteration of gene, protein expression, and metabolism induced by GNP administration. , The serum protein adsorption on PEG-GNPs may contribute to the increase in protein content in the deposited sites. Recently, several evidence suggest that lipids, nucleic acids, and metabolites can also interact with the surface of NPs . In our previous research, we found PEG-GNPs to mainly deposit in the liver and could subsequently induce the elevation of gene expression of drug-metabolizing enzymes including cytochrome P450 (CYP450) isoforms, phase II metabolized enzymes UDP-glucuronosyltransferases (UGT), and drug uptake and efflux transporters including P-glycoprotein (P-gp), organic cation transporter 1 (OCT1), and organic anion transporters (OATs) after i.v.…”

Section: Discussionmentioning

confidence: 99%

Multiscale Synchrotron-Based Imaging Analysis for the Transfer of PEGylated Gold Nanoparticles In Vivo

Xue

Wang

et al. 2021

ACS Biomater. Sci. Eng.

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High spatial resolution imaging analysis is urgently needed to explore the biodistribution, transfer and clearance profiles, and biological impact of nanoparticles in the body, which will be helpful to clarify the efficacy of nanomedicine in clinical applications. Herein, by combination with multiscale synchrotron-based imaging techniques, including X-ray fluorescence (XRF) spectrometry, Fourier transform infrared (FTIR) spectroscopy, and micro X-ray phase contrast computed tomography (micro-XPCT), we visually displayed the transfer patterns and site-specific distribution of PEGylated gold nanoparticles (PEG-GNPs) in the suborgans of the liver, spleen, and kidney after an intravenous injection in mice. A combination of XRF and FTIR imaging analysis showed that the PEG bands presented similar distribution patterns with Au in the intraorgans, suggesting the stability of PEGylation on GNPs. We show that the PEG-GNPs presented heterogeneous distribution in the hepatic lobules with a large amount around the portal vein zone and then a gradient decrease in the sinusoidal region and the CV zone; in the spleen, it gradually accumulated in the splenic red pulp over time; and in the kidney, it quickly transported via the bloodstream to the renal pyramids and renal pelvis, and parts of PEG-GNPs finally accumulated in the renal medulla and renal cortex. Multidimensional micro-XPCT images further show that the PEG-GNP transfer in the liver induced hepatic blood vessel dilatation while they transferred in the liver, providing evidence of GNP transport across the blood vessel endothelial barrier.

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“…Moreover, EV isolates often contain lipoproteins, protein aggregates, and nonvesicle macromolecules (Sunkara et al, 2016). We also know that cell-free DNA can adsorb to lipid nanoparticles (Gardner et al, 2020), which is likely to occur for circulating EVs too, but surprisingly, this phenomenon is largely overlooked in the field. These "contaminants" influence the biological function Abbreviations: AFM, atomic force microscopy; AFM-IR, atomic force microscope infrared-spectroscopy; CMSC29, chorionic mesenchymal stromal/stem cell line; CEVs, extracellular vesicles derived from chorionic mesenchymal stromal/stem cell; DMSC23, decidual mesenchymal stromal/stem cell line; DEVs, extracellular vesicles derived from decidual mesenchymal stromal/stem cell; EVs, extracellular vesicles; HBSS(-), Hank's balanced salt solution; LPS, lipopolysaccharide; MSC, mesenchymal stromal/stem cell; PTA, particle tracking analysis; nFCM, nanoflow cytometry; RMM, resonant mass measurement; TRPS, tunable resistive pulse sensing; TFF, tangential flow filtration.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, EV isolates often contain lipoproteins, protein aggregates, and non-vesicle macromolecules ( Sunkara et al, 2016 ). We also know that cell-free DNA can adsorb to lipid nanoparticles ( Gardner et al, 2020 ), which is likely to occur for circulating EVs too, but surprisingly, this phenomenon is largely overlooked in the field. These “contaminants” influence the biological function of EVs and are not trivial to detect due to the sensitivity of experimental methods.…”

Section: Introductionmentioning

confidence: 99%

New Multiscale Characterization Methodology for Effective Determination of Isolation–Structure–Function Relationship of Extracellular Vesicles

Phan

Divakarla

Yeo

et al. 2021

Front. Bioeng. Biotechnol.

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Extracellular vesicles (EVs) have been lauded as next-generation medicines, but very few EV-based therapeutics have progressed to clinical use. Limited clinical translation is largely due to technical barriers that hamper our ability to mass produce EVs, i.e., to isolate, purify, and characterize them effectively. Technical limitations in comprehensive characterization of EVs lead to unpredicted biological effects of EVs. Here, using a range of optical and non-optical techniques, we showed that the differences in molecular composition of EVs isolated using two isolation methods correlated with the differences in their biological function. Our results demonstrated that the isolation method determines the composition of isolated EVs at single and sub-population levels. Besides the composition, we measured for the first time the dry mass and predicted sedimentation of EVs. These parameters were likely to contribute to the biological and functional effects of EVs on single cell and cell cultures. We anticipate that our new multiscale characterization approach, which goes beyond traditional experimental methodology, will support fundamental understanding of EVs as well as elucidate the functional effects of EVs in in vitro and in vivo studies. Our findings and methodology will be pivotal for developing optimal isolation methods and establishing EVs as mainstream therapeutics and diagnostics. This innovative approach is applicable to a wide range of sectors including biopharma and biotechnology as well as to regulatory agencies.

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The biomolecule corona of lipid nanoparticles contains circulating cell-free DNA

Abstract: The biomolecule corona spontaneously adsorbed onto lipid-based nanoparticles (NPs), upon incubation with human plasma, contains circulating cell-free DNA (cfDNA).

Cited by 21 publications

References 70 publications

Nanoparticle-Enabled Enrichment of Longitudinal Blood Proteomic Fingerprints in Alzheimer’s Disease

Nanoparticle-Enabled Enrichment of Longitudinal Blood Proteomic Fingerprints in Alzheimer’s Disease

Multiscale Synchrotron-Based Imaging Analysis for the Transfer of PEGylated Gold Nanoparticles In Vivo

New Multiscale Characterization Methodology for Effective Determination of Isolation–Structure–Function Relationship of Extracellular Vesicles

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