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Soluble oligomers populating early amyloid aggregation can be regarded as nanodroplets of liquid-liquid phase separation (LLPS). Amyloid peptides typically contain hydrophobic aggregation-prone regions connected by hydrophilic linkers and flanking sequences, and such a sequence hydropathy pattern drives the formation of supramolecular structures in the nanodroplets and modulates subsequent fibrillization. Here, we studied LLPS and fibrillization of coarse-grained amyloid peptides with increasing flanking sequences. Nanodroplets assumed lamellar, cylindrical micellar, and spherical micellar structures with increasing peptide hydrophilic/hydrophobic ratios, and such morphologies governed subsequent fibrillization processes. Adding glycine-serine repeats as flanking sequences to Aβ

Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the in vivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.

An inconvenient hurdle in the practice of nanomedicine is the protein corona, a spontaneous collection of biomolecular species by nanoparticles in living systems. The protein corona is dynamic in composition and may entail improved water suspendability and compromised delivery and targeting to the nanoparticles. How much of this nonspecific protein ensemble is determined by the chemistry of the nanoparticle core and its surface functionalization, and how much of this entity is dictated by the biological environments that vary spatiotemporally

Much has been learned about the protein coronae and their biological implications within the context of nanomedicine and nanotoxicology. However, no data is available about the protein coronae associated with nanoparticles undergoing spontaneous surface-energy minimization, a common phenomenon during the synthesis and shelf life of nanomaterials. Accordingly, here we employed gold nanoparticles (AuNPs) possessing the three initial states of spiky, midspiky, and spherical shapes and determined their acquisition of human plasma protein coronae with label-free mass spectrometry. The AuNPs collected coronal proteins that were different in abundance, physicochemical parameters, and interactive biological network. The size and structure of the coronal proteins matched the morphology of the AuNPs, where small globular proteins and large fibrillar proteins were enriched on spiky AuNPs, while large proteins were abundant on spherical AuNPs. Furthermore, the AuNPs induced endothelial leakiness to different degrees, which was partially negated by their protein coronae as revealed by confocal fluorescence microscopy, in vitro and ex vivo transwell assays, and signaling pathway assays. This study has filled a knowledge void concerning the dynamic protein corona of nanoparticles possessing an evolving morphology and shed light on their implication for future nanomedicine harnessing the paracellular pathway.

Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer’s disease (AD), Parkinson’s disease (PD), and type 2 diabetes (T2D), three primary forms of human amyloid diseases. While much has been learned about the origin, diagnosis, and management of these neurological and metabolic disorders, no cure is currently available due in part to the dynamic and heterogeneous nature of the toxic oligomers induced by amyloid aggregation. Here, we synthesized β-casein-coated iron oxide nanoparticles (βCas IONPs) via a 2-(bis-((phosphonic acid)methyl)amino)ethyl-(poly(oligo ethylene glycol)methyl ether acrylate)-b-(poly(N-ethyl-2,3-dibromomaleimide)acrylate)-((butylthio)-carbonothioyl)thio propionate (BPA-P(OEGA-b-DBM)) block copolymer linker. Using a thioflavin T kinetic assay, transmission electron microscopy, Fourier transform infrared spectroscopy, discrete molecular dynamics simulations, and cell viability assays, we examined the Janus characteristics and the inhibition potential of βCas IONPs against the aggregation of amyloid β (Aβ), α synuclein (αS), and human islet amyloid polypeptide (IAPP), which are implicated in the pathologies of AD, PD, and T2D. Incubation of zebrafish embryos with the amyloid proteins largely inhibited hatching and elicited reactive oxygen species, which were effectively rescued by the inhibitor. Furthermore, Aβ-induced damage to the mouse brain was mitigated in vivo with the inhibitor. This study revealed the potential of Janus nanoparticles as a new nanomedicine against a diverse range of amyloid diseases.

Alzheimer’s disease (AD) is a major cause of dementia characterized by the overexpression of transmembrane amyloid precursor protein and its neurotoxic byproduct amyloid beta (Aβ). A small peptide of considerable hydrophobicity, Aβ is aggregation prone catalyzed by the presence of cell membrane, among other environmental factors. Accordingly, current AD mitigation strategies often take aim at breaking down the Aβ-membrane communication, yet no data is available concerning the cohesive interplay of the three key entities of cell membrane, Aβ, and its inhibitor. Using a lipophilic Laurdan dye and confocal fluorescence microscopy, we observed cell membrane perturbation and actin reorganization induced by Aβ oligomers, but not by Aβ monomers or amyloid fibrils. We further revealed recovery of membrane fluidity by ultrasmall MoS(2) quantum dots, also shown in this study as a potent inhibitor of Aβ amyloid aggregation. Using discrete molecular dynamics simulations, we uncovered the binding of MoS(2) and Aβ monomers as mediated by hydrophilic interactions between the quantum dots and the peptide N-terminus. In contrast, Aβ oligomers and fibrils were surface-coated by the ultrasmall quantum dots in distinct testudo-like, reverse protein-corona formations to prevent their further association with cell membrane and adverse effects downstream. This study offered a crucial new insight and a viable strategy for regulating the amyloid aggregation and membrane-axis of AD pathology with multifunctional nanomedicine.

The nanomaterial–protein “corona” is a dynamic entity providing a synthetic–natural interface mediating cellular uptake and subcellular distribution of nanomaterials in biological systems. As nanomaterials are central to the safe-by-design of future nanomedicines and the practice of nanosafety, understanding and delineating the biological and toxicological signatures of the ubiquitous nanomaterial–protein corona are precursors to the continued development of nano–bio science and engineering. However, despite well over a decade of extensive research, the dynamics of intracellular release or exchange of the blood protein corona from nanomaterials following their cellular internalization remains unclear, and the biological footprints of the nanoparticle–protein corona traversing cellular compartments are even less well understood. To address this crucial bottleneck, the current work screened evolution of the intracellular protein corona along the endocytotic pathway from blood via lysosomes to cytoplasm in cancer cells. Intercellular proteins, including pyruvate kinase M2 (PKM2), and chaperones, displaced some of the initially adsorbed blood proteins from the nanoparticle surface, which perturbed proteostasis and subsequently incited chaperone-mediated autophagy (CMA) to disrupt the key cellular metabolism pathway, including glycolysis and lipid metabolism. Since proteostasis is key to the sustainability of cell function, its collapse and the resulting CMA overdrive spell subsequent cell death and aging. Our findings shed light on the consequences of the transport of extracellular proteins by nanoparticles on cell metabolism.

Amyloid diseases are global epidemics characterized by the accumulative deposits of cross-beta amyloid fibrils and plaques. Despite decades of intensive research, few solutions are available for the diagnosis, treatment, and prevention of these debilitating diseases. Since the early work on the interaction of human β2-microglobulin and nanoparticles by Linse et al. in 2007, the field of amyloidosis inhibition has gradually evolved into a new frontier in nanomedicine offering numerous interdisciplinary research opportunities, especially for materials, chemistry and biophysics. In this review we summarise, for the first time, the in vitro and in vivo models employed thus far in the field of anti-amyloidosis nanomedicines. Based on this systematic summary, we bring forth the notion that, due to the complex and often overlapping physiopathologies of amyloid diseases, there is a crucial need for the appropriate use of in vitro and in vivo models for validating novel anti-amyloidosis nanomedicines, and there is a crucial need for the development of new animal models that reflect the behavioural, symptomatic and cross-talk hallmarks of amyloid diseases such as Alzheimer's (AD), Parkinson's (PD) diseases and type 2 diabetes (T2DM).

Increasing experiments suggest that amyloid peptides can undergo liquid-liquid phase separation (LLPS) before the formation of amyloid fibrils. However, the exact role of LLPS in amyloid aggregation at the molecular level remains elusive. Here, we investigated the LLPS and amyloid fibrillization of a coarse-grained peptide, capable of capturing fundamental properties of amyloid aggregation over a wide range of concentrations in molecular dynamics simulations. On the basis of the Flory-Huggins theory of polymer solutions, we determined the binodal and spinodal concentrations of LLPS in the low-concentration regime, ϕBL and ϕSL, respectively. Only at concentrations above ϕBL, peptides formed metastable or stable oligomers corresponding to the high-density liquid phase (HDLP) in LLPS, out of which the nucleated conformational conversion to fibril seeds occurred. Below ϕSL, the HDLP was metastable and transient, and the subsequent fibrillization process followed the traditional nucleation and elongation mechanisms. Only above ϕSL, the HDLP became stable, and the initial fibril nucleation and growth were governed by the high local peptide concentrations. The predicted saturation of amyloid aggregation half-times with increasing peptide concentration to a constant, instead of the traditional power-law scaling to zero, was confirmed by simulations and by a thioflavin-T kinetic assay and the transmission electron microscopy of islet amyloid polypeptide (IAPP) aggregation. Our study provides a unified picture of amyloid aggregation for a wide range of concentrations within the framework of LLPS, which may help us better understand the etiology of amyloid diseases, where the amyloid protein concentration can vary by ∼9 orders of magnitude depending on the organ location and facilitate the engineering of novel amyloid-based functional materials.

Nanoparticles (NPs) can make their way to the brain and cause

Type 2 diabetes (T2D) is a metabolic disease and a global health crisis. Because of the small mass and high dispersity of beta cells in the pancreas, especially among T2D patients, it remains a tre...

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 – Aβ(1–42) and Aβ(1–40) – exposed to human blood plasma. Out of the proteins identified in all groups, 58 proteins were unique to the Aβ(1–42) samples and 31 proteins unique to the Aβ(1–40) 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 multi domains of high flexibility to maximize their association with the amyloid fibrils. The protein corona hindered recognition of Aβ(1–42) fibrils by their structurally specific antibodies, and accelerated the aggregation but not β-cell toxicity of human islet amyloid polypeptide (IAPP), 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.

Amyloid diseases are global epidemics with no cure currently available. In the past decade, the use of engineered nanomaterials as inhibitors or probes against the pathogenic aggregation of amyloid peptides and proteins has emerged as a new frontier in nanomedicine. In this Minireview, we summarize for the first time the pivotal role of chemical synthesis in enabling the development of this multidisciplinary field.

Alzheimer’s disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aβ deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid proteins-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings are analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred with the anionic seeds of pathogenic alpha synuclein and functional FapC bacterial amyloid, this study projects a general new paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD, Parkinson’s, as well as a range of amyloid diseases.

Alzheimer's disease (AD) is a primary form of dementia with debilitating consequences, but no effective cure is available. While the pathophysiology of AD remains multifactorial, the aggregation of amyloid beta (Aβ) mediated by the cell membrane is known to be the cause for the neurodegeneration associated with AD. Here we examined the effects of graphene quantum dots (GQDs) on the obstruction of the membrane axis of Aβ in its three representative forms of monomers (Aβ-m), oligomers (Aβ-o), and amyloid fibrils (Aβ-f). Specifically, we determined the membrane fluidity of neuroblastoma SH-SY5Y cells perturbed by the Aβ species, especially by the most toxic Aβ-o, and demonstrated their recovery by GQDs using confocal fluorescence microscopy. Our computational data through discrete molecular dynamics simulations further revealed energetically favorable association of the Aβ species with the GQDs in overcoming peptide-peptide aggregation. Overall, this study positively implicated GQDs as an effective agent in breaking down the membrane axis of Aβ, thereby circumventing adverse downstream events and offering a potential therapeutic solution for AD.

The global-scale production of plastics has been instrumental in advancing modern society, while the rising accumulation of plastics in landfills, oceans, and anything in between has become a major stressor on environmental sustainability, climate, and, potentially, human health. While mechanical and chemical forces of man and nature can eventually break down or recycle plastics, our understanding of the biological fingerprints of plastics, especially of nanoplastics, remains poor. Here we report on a phenomenon associated with the nanoplastic forms of anionic polystyrene and poly(methyl methacrylate), where their introduction disrupted the vascular endothelial cadherin junctions in a dose-dependent manner, as revealed by confocal fluorescence microscopy, signaling pathways, molecular dynamics simulations, as well as ex vivo and in vivo assays with animal model systems. Collectively, our results implicated nanoplastics-induced vasculature permeability as primarily biophysical-biochemical in nature, uncorrelated with cytotoxic events such as reactive oxygen species production, autophagy, and apoptosis. This uncovered route of paracellular transport has opened up vast avenues for investigating the behaviour and biological effects of nanoplastics, which may offer crucial insights for guiding innovations towards a sustainable plastics industry and environmental remediation.

The rapid development of nanotechnology has greatly benefited modern science and engineering and also led to an increased environmental exposure to nanoparticles (NPs). While recent research has established a correlation between the exposure of NPs and cardiovascular diseases, the intrinsic mechanisms of such a connection remain unclear. Inhaled NPs can penetrate the air-blood barrier from the lung to systemic circulation, thereby intruding the cardiovascular system and generating cardiotoxic effects. In this study, on-site cardiovascular damage was observed in mice upon respiratory exposure of silica nanoparticles (SiNPs), and the corresponding mechanism was investigated by focusing on the interaction of SiNPs and their encountered biomacromolecules en route. SiNPs were found to collect a significant amount of apolipoprotein A-I (Apo A-I) from the blood, in particular when the SiNPs were preadsorbed with pulmonary surfactants. While the adsorbed Apo A-I ameliorated the cytotoxic and proinflammatory effects of SiNPs, the protein was eliminated from the blood upon clearance of the NPs. However, supplementation of Apo A-I mimic peptide mitigated the atherosclerotic lesion induced by SiNPs. In addition, we found a further declined plasma Apo A-I level in clinical silicosis patients than coronary heart disease patients, suggesting clearance of SiNPs sequestered Apo A-I to compromise the coronal protein's regular biological functions. Together, this study has provided evidence that the protein corona of SiNPs acquired in the blood depletes Apo A-I, a biomarker for prediction of cardiovascular diseases, which gives rise to unexpected toxic effects of the nanoparticles.

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 Aβ(1–42)(Aβ(f)), 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 Aβ(f) showed a clear preference for binding with all cell types sans plasma proteins. Immune cells exposed to Aβo, but not to Aβ(f), 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 Aβ(f) and shed new light on the contrasting toxicities of Aβo and Aβ(f) 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.

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more α-helices than β-sheets, consistent with ensemble-based experimental measurements. However, in ~4–6% independent simulations, β-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These β-rich oligomers could adopt β-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these β-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. β-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.

Although much has been learned about the fibrillization kinetics, structure and toxicity of amyloid proteins, the properties of amyloid fibrils beyond the saturation phase are often perceived as chemically and biologically inert, despite evidence suggesting otherwise. To fill this knowledge gap, we examined the physical and biological characteristics of human islet amyloid polypeptide (IAPP) fibrils that were aged up to two months. Not only did aging decrease the toxicity of IAPP fibrils, but the fibrils also sequestered fresh IAPP and suppressed their toxicity in an embryonic zebrafish model. The mechanical properties of IAPP fibrils in different aging stages were probed by atomic force microscopy and sonication, which displayed comparable stiffness but age-dependent fragmentation, followed by self-assembly of such fragments into the largest lamellar amyloid structures reported to date. The dynamic structural and toxicity profiles of amyloid fibrils and plaques suggest that they play active, long-term roles in cell degeneration and may be a therapeutic target for amyloid diseases.

Featuring small sizes, caged structures, low cytotoxicity and the capability to cross biological barriers, fullerene hydroxy derivatives named fullerenols have been explored as nanomedicinal candidates for amyloid inhibition. Understanding the surface chemistry effect of hydroxylation extents and the corresponding amyloid inhibition mechanisms is necessary for enabling applications of fullerenols and also future designs of nanomedicines in mitigating amyloid aggregation. Here, we investigated effects of C60(OH)n with n = 0-40 on the aggregation of NACore (the amyloidogenic core region of the non-amyloid-β component in α-synuclein), the amyloidogenic core of α-synuclein, by computational simulations, transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, thioflavin-T (ThT) fluorescence kinetics and viability assays. Computationally, NACore assembled into cross-β aggregates via intermediates including β-barrels, which are postulated as toxic oligomers of amyloid aggregation. Hydrophobic C60 preferred to self-assemble, and NACore bound to the surface of C60 nano-clusters formed β-sheet rich aggregates - i.e., having little inhibition effect. Amphiphilic C60(OH)n with n = 4-20 displayed significant inhibition effects on NACore aggregation, where hydrogen bonding between hydroxyls and peptide backbones interrupted the formation of β-sheets between peptides adsorbed onto the surfaces of fullerenols or fullerenol nano-assemblies due to hydrophobic interactions. Thus, both cross-β aggregates and β-barrel intermediates were significantly suppressed. With hydroxyls increased to 40, fullerenols became highly hydrophilic with reduced peptide binding and thus an inhibition effect on amyloid aggregation. ThT, FTIR and TEM characterization of C60(OH)n with n = 0, 24, & 40 confirmed the computational predictions. Our results and others underscore the importance of amphiphilic surface chemistry and the capability of polar groups in forming hydrogen bonds with peptide backbones to render amyloid inhibition, offering a new insight for de-novo design of anti-amyloid inhibitors.

The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.

Nanotoxicology and nanomedicine are two sub-disciplines of nanotechnology focusing on the phenomena, mechanisms, and engineering at the nano-bio interface. For the better part of the past three decades, these two disciplines have been largely developing independently of each other. Yet recent breakthroughs in microbiome research and the current COVID-19 pandemic demonstrate that holistic approaches are crucial for solving grand challenges in global health. Here we show the Yin and Yang relationship between the two fields by highlighting their shared goals of making safer nanomaterials, improved cellular and organism models, as well as advanced methodologies. We focus on the transferable knowledge between the two fields as nanotoxicological research is moving from pristine to functional nanomaterials, while inorganic nanomaterials – the main subjects of nanotoxicology – have become an emerging source for the development of nanomedicines. We call for a close partnership between the two fields in the new decade, to harness the full potential of nanotechnology for benefiting human health and environmental safety.

Soluble low-molecular-weight oligomers formed during the early aggregation of amyloid peptides have been hypothesized as a major toxic species of amyloidogenesis. Herein, we performed the first synergic in silico, in vitro and in vivo validations of the structure, dynamics and toxicity of Aβ42 oligomers. Aβ peptides readily assembled into β-rich oligomers comprised of extended β-hairpins and β-strands. Nanosized β-barrels were observed with certainty with simulations, transmission electron microscopy and Fourier transform infrared spectroscopy, corroborated by immunohistochemistry, cell viability, apoptosis, inflammation, autophagy and animal behavior assays. Secondary and tertiary structural proprieties of these oligomers, such as the sequence regions with high β-sheet propensities and inter-residue contact frequency patterns, were similar to the properties known for Aβ fibrils. The unambiguous spontaneous formation of β-barrels in the early aggregation of Aβ42 supports their roles as the common toxic intermediates in Alzheimer's pathobiology and a target for Alzheimer's therapeutics.

Alzheimer's disease (AD) is a major neurological disorder impairing its carrier's cognitive function, memory, and lifespan. While the development of AD nanomedicine is still nascent, the field is evolving into a new scientific frontier driven by the diverse physicochemical properties and theranostic potential of nanomaterials and nanocomposites. Characteristic to the AD pathology is the deposition of amyloid plaques and tangles of amyloid beta (Aβ) and tau, whose aggregation kinetics may be curbed by nanoparticle inhibitors via sequence‐specific targeting or nonspecific interactions with the amyloidogenic proteins. As literature implicates cell membrane as a culprit in AD pathogenesis, herein, the membrane axis of AD nanomedicine is summarized and a new rationale that the field development may greatly benefit from harnessing our existing knowledge of Aβ‐membrane interaction, nanoparticle–membrane interaction, and Aβ–nanoparticle interaction is presented.

Recent clinical and pathological evidence have implicated the gut microbiota as a nexus for modulating the homeostasis of the human body, impacting conditions from cancer and dementia to obesity and social behavior. The connections between microbiota and human diseases offer numerous opportunities in medicine, most of which have limited or no therapeutic solutions available. In light of this paradigm-setting trend in science, this review aims to provide a comprehensive and timely summary of the mechanistic pathways governing the gut microbiota and their implications for nanomedicines targeting cancer and neurodegenerative diseases. Specifically, we discuss in parallel the beneficial and pathogenic relationship of the gut microbiota along the gut-brain and gut-cancer axes, elaborate on the impact of dysbiosis and the gastrointestinal corona on the efficacy of nanomedicines, and highlight a molecular mimicry that manipulates the universal cross-β backbone of bacterial amyloid to accelerate neurological disorders. This review further offers a forward-looking section on the rational design of cancer and dementia nanomedicines exploiting the gut-brain and gut-cancer axes.

In article number 2001299, Thomas P. Davis, Feng Ding, Pu Chun Ke, and co‐workers examine the aggregation of amyloid beta, the pathogenic peptide associated with Alzheimer's disease, seeded by the amyloid fragments of FapC, a protein constituent of the extracellular matrix of Pseudomonas aeruginosa that colonizes the gut microbiome through infection. [Image: see text]

The protein corona has served as a central dogma and a nuisance to the applications of nanomedicine and nanobiotechnology for well over a decade. Here we introduce the emerging field of amyloidosis inhibition, which aims to understand and harness the interfacial phenomena associated with a nanoparticle interacting with pathogenic amyloid proteins. Much of this interaction correlates with our understanding of the protein corona, and yet much differs, as elaborated for the first time in this Perspective. Specifically, we examine the in vitro, in silico and in vivo features of the new class of "amyloid protein corona", and discuss how the interactions with nanoparticles may halt the self-assembly of amyloid proteins. As amyloidosis is driven off pathway by the nanoparticles, the oligomeric and protofibrillar populations are suppressed to ameliorate their cytotoxicity. Furthermore, as amyloid proteins spread via the transport of bodily fluids or cross seeding, amyloidosis is inherently associated with dynamic proteins and ligands to evoke the immune system. Accordingly, we ponder the structural and medical implications of the amyloid protein corona in the presence of their stimulated cytokines. Understanding and exploiting the amyloid protein corona may facilitate the development of new theranostics against a range of debilitating amyloid diseases.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) represent two most prevalent amyloid diseases with a significant global burden. Pathologically, T2D and AD are characterized by the presence of amyloid plaques consisting primarily of toxic human islet amyloid polypeptide (IAPP) and amyloid beta (Aβ). It has been recently revealed that the gut microbiome plays key functions in the pathological progression of neurological disorders through the production of bacterial endotoxins, such as lipopolysaccharide (LPS). In this study, we examined the catalytic effects of LPS on IAPP and Aβ amyloidoses, and further demonstrated their mitigation with zero-dimensional carbon quantum dots (CQDs). Whereas LPS displayed preferred binding with the N-terminus of IAPP and the central hydrophobic core and C-terminus of Aβ, CQDs exhibited propensities for the amyloidogenic and C-terminus regions of IAPP and the N-terminus of Aβ, accordingly. The inhibitory effect of CQDs was verified by an embryonic zebrafish model exposed to the peptides and LPS, where impaired embryonic hatching was rescued and production of reactive oxygen species in the organism was suppressed by the nanomaterial. This study revealed a robust synergy between LPS and amyloid peptides in toxicity induction, and implicated CQDs as a potential therapeutic against the pathologies of T2D and AD.

The protein corona is a concept central to a range of disciplines exploiting the bio–nano interface. As the literature continues to expand in this field, it is essential to condense and contextualize the in vitro and in vivo proteome databases accumulated over the past decade: a goal which this review intends to achieve for the benefit of nanomedicine and nanobiotechnology. The parameters used for our review are the physicochemical characteristics of the nanoparticles, their surface ligands, the biological matrixfrom which a corona was formed, methods employed, plus the top-ten enriched corona proteins. In addition, the protein coronal networks and their implications in vivo are highlighted for selected studies. Refereed/Peer-reviewed

Contains fulltext : 229460.pdf (Publisher’s version ) (Closed access) A common feature in the pathophysiology of different types of diabetes is the reduction of beta cell mass and/or impairment of beta cell function. Diagnosis and treatment of type 1 and type 2 diabetes is currently hampered by a lack of reliable techniques to restore beta cell survival, to improve insulin secretion, and to quantify beta cell mass in patients. Current new approaches may allow us to precisely and specifically visualize beta cells in vivo and provide viable therapeutic strategies to preserve, recover, and regenerate beta cells. In this review, we discuss recent protective approaches for beta cells and the advantages and limitations of current imaging probes in the field.

The gut–brain axis has attracted increasing attention in recent years, fueled by accumulating symptomatic, physiological, and pathological findings. In this study, the aggregation and toxicity of amyloid beta (Aβ ), the pathogenic peptide associated with Alzheimer's disease (AD), seeded by FapC amyloid fragments (FapCS) of Pseudomonas aeruginosa that colonizes the gut microbiome through infections are examined. FapCS display favorable binding with Aβ and a catalytic capacity in seeding the peptide amyloidosis. Upon seeding, twisted Aβ fibrils assume a much‐shortened periodicity approximating that of FapC fibrils, accompanied by a 37% sharp rise in the fibrillar diameter, compared with the control. The robust seeding capacity for Aβ by FapCS and the biofilm fragments derived from P. aeruginosa entail abnormal behavior pathology and immunohistology, as well as impaired cognitive function of zebrafish. Together, the data offer the first concrete evidence of structural integration and inheritance in peptide cross‐seeding, a crucial knowledge gap in understanding the pathological correlations between different amyloid diseases. The catalytic role of infectious bacteria in promoting Aβ amyloidosis may be exploited as a potential therapeutic target, while the altered mesoscopic signatures of Aβ fibrils may serve as a prototype for molecular assembly and a biomarker for screening bacterial infections in AD., Advanced Science, 7 (18), ISSN:2198-3844

Protein aggregation is a ubiquitous phenomenon underpinning the origins of a range of human diseases. The amyloid aggregation of human islet amyloid polypeptide (IAPP) and alpha synuclein (αS), specifically, is a hallmark of type 2 diabetes (T2D) and Parkinson's disease impacting millions of people worldwide. Although IAPP and αS are strongly associated with pancreatic β-cell islets and presynaptic terminals, they have also been found in blood circulation and the gut. While extensive biophysical and biochemical studies have been focused on IAPP and αS interacting with cell membranes or model lipid vesicles, the roles of plasma proteins on the amyloidosis and membrane association of these two major types of amyloid proteins have rarely been examined. Using a thioflavin T kinetic assay, transmission electron microscopy and a hemolysis assay here we show that human serum albumin, the most abundant protein in the plasma, impeded the fibrillization and mitigated membrane damage of both IAPP and αS. This study offers a new insight on the native inhibition of amyloidosis.

Amyloid diseases are global epidemics with no cure available. Herein, we report a first demonstration of in vivo mitigation of amyloidogenesis using biomimetic nanotechnology. Specifically, the amyloid fragments (ba) of β-lactoglobulin, a whey protein, were deposited onto the surfaces of carbon nanotubes (baCNT), which subsequently sequestered human islet amyloid polypeptide (IAPP) through functional-pathogenic double-protein coronae. Conformational changes at the ba–IAPP interface were studied by Fourier transform infrared, circular dichroism, and X-ray scattering spectroscopies. baCNT eliminated the toxic IAPP species from zebrafish embryos, as evidenced by the assays of embryonic development, cell morphology, hatching, and survival as well as suppression of oxidative stress. In addition to IAPP, baCNT also displayed high potency against the toxicity of amyloid-β, thereby demonstrating the broad applicability of this biomimetic nanotechnology and the use of an embryonic zebrafish model for the high-thro...

Amyloids may be regarded as native nanomaterials that form in the presence of complex protein mixtures. By drawing an analogy with the physicochemical properties of nanoparticles in biological fluids, we hypothesized that amyloids should form a protein corona in vivo that would imbue the underlying amyloid with a modified biological identity. To explore this hypothesis, we characterized the protein corona of human islet amyloid polypeptide (IAPP) fibrils in fetal bovine serum using two complementary methodologies developed herein: quartz crystal microbalance and "centrifugal capture", coupled with nanoliquid chromatography tandem mass spectroscopy. Clear evidence for a significant protein corona was obtained. No trends were identified for amyloid corona proteins based on their physicochemical properties, whereas strong binding with IAPP fibrils occurred for linear proteins or multidomain proteins with structural plasticity. Proteomic analysis identified amyloid-enriched proteins that are known to play significant roles in mediating cellular machinery and processing, potentially leading to pathological outcomes and therapeutic targets. Refereed/Peer-reviewed