Endothelial leakiness elicited by amyloid protein aggregation.

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 (Aß) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aß deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-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 Aß oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were 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 in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD and Parkinson's disease.

Alzheimer's Progenitor Amyloid-ß Targets and Dissolves Microbial Amyloids and Impairs Biofilm Function.

Alzheimer's disease (AD) is a leading form of dementia where the presence of extra-neuronal plaques of Amyloid-ß (Aß) is a pathological hallmark. However, Aß peptide is also observed in the intestinal tissues of AD patients and animal models. In this study, it is reported that Aß monomers can target and disintegrate microbial amyloids of FapC and CsgA formed by opportunistic gut pathogens, Pseudomonas aeruginosa and Escherichia coli, explaining a potential role of Aß in the gut-brain axis. Employing a zebrafish-based transparent in vivo system and whole-mount live-imaging, Aß is observed to diffuse into the vasculature and subsequently localize with FapC or CsgA fibrils that were injected into the tail muscles of the fish. FapC aggregates, produced after Aß treatment (Faß), present selective toxicity to SH-SY5Y neuronal cells while the intestinal Caco-2 cells are shown to phagocytose Faß in a non-toxic cellular process. After remodeling by Aß, microbial fibrils lose their native function of cell adhesion with intestinal Caco-2 cells and Aß dissolves and detaches the microbial fibrils already attached to the cell membrane. Taken together, this study strongly indicates an anti-biofilm role for Aß monomers that can help aid in the future development of selective anti-Alzheimer's and anti-infective medicine.

Keeping up with the COVID's-Could siRNA-based antivirals be a part of the answer?

Coronavirus disease 2019 (COVID-19) is a highly contagious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This deadly infection has resulted in more than 5.2 million deaths worldwide. The global rollout of COVID-19 vaccines has without doubt saved countless lives by reducing the severity of symptoms for patients. However, as the virus continues to evolve, there is a risk that the vaccines and antiviral designed to target the infection will no longer be therapeutically viable. Furthermore, there remain fears over both the short and long-term side effects of repeat exposure to currently available vaccines. In this review, we discuss the pros and cons of the vaccine rollout and promote the idea of a COVID medicinal toolbox made up of different antiviral treatment modalities, and present some of the latest therapeutic strategies that are being explored in this respect to try to combat the COVID-19 virus and other COVID viruses that are predicted to follow. Lastly, we review current literature on the use of siRNA therapeutics as a way to remain adaptable and in tune with the ever-evolving mutation rate of the COVID-19 virus.

Inhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles.

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 beta casein-coated iron oxide nanoparticles (ßCas IONPs) via a 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 ßCas IONPs against the aggregation of amyloid beta (Aß), alpha 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, Aß-induced damage to 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.

Graphene quantum dots obstruct the membrane axis of Alzheimer's amyloid beta.

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 (Aß) 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 Aß in its three representative forms of monomers (Aß-m), oligomers (Aß-o), and amyloid fibrils (Aß-f). Specifically, we determined the membrane fluidity of neuroblastoma SH-SY5Y cells perturbed by the Aß species, especially by the most toxic Aß-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 Aß 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 Aß, thereby circumventing adverse downstream events and offering a potential therapeutic solution for AD.

Dynamic Protein Corona of Gold Nanoparticles with an Evolving Morphology.

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.

Structure Dependent Differential Modulation of Aß Fibrillization by Selenadiazole-Based Inhibitors.

Misfolding and fibrillar aggregation of Aß is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aß are designed to sequester and clear Aß burden from the neurological tissues. Based on the physiological relevance of Aß, therapeutic approaches are required to inhibit and stabilize Aß fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aß. Compounds that completely inhibited the Aß fibrillization appeared to stabilize Aß at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aß into smaller fragments with slightly higher ß-sheets contents, while noninhibitors did not interfere in Aß aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aß control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aß toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aß peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aß monomers displayed higher association constants (Ka) and lower dissociation constants (Kd) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.

A Framework of Paracellular Transport via Nanoparticles-Induced Endothelial Leakiness.

Nanomaterial-induced endothelial leakiness (NanoEL) is an interfacial phenomenon denoting the paracellular transport of nanoparticles that is pertinent to nanotoxicology, nanomedicine and biomedical engineering. While the NanoEL phenomenon is complementary to the enhanced permeability and retention effect in terms of their common applicability to delineating the permeability and behavior of nanoparticles in tumoral environments, these two effects significantly differ in scope, origin, and manifestation. In the current study, the descriptors are fully examined of the NanoEL phenomenon elicited by generic citrate-coated gold nanoparticles (AuNPs) of changing size and concentration, from microscopic gap formation and actin reorganization down to molecular signaling pathways and nanoscale interactions of AuNPs with VE-cadherin and its intra/extracellular cofactors. Employing synergistic in silico methodologies, for the first time the molecular and statistical mechanics of cadherin pair disruption, especially in response to AuNPs of the smallest size and highest concentration are revealed. This study marks a major advancement toward establishing a comprehensive NanoEL framework for complementing the understanding of the transcytotic pathway and for guiding the design and application of future nanomedicines harnessing the myriad functions of the mammalian vasculature.

Ultrasmall Molybdenum Disulfide Quantum Dots Cage Alzheimer's Amyloid Beta to Restore Membrane Fluidity.

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 (Aß). A small peptide of considerable hydrophobicity, Aß is aggregation prone catalyzed by the presence of cell membranes, among other environmental factors. Accordingly, current AD mitigation strategies often aim at breaking down the Aß-membrane communication, yet no data is available concerning the cohesive interplay of the three key entities of the cell membrane, Aß, and its inhibitor. Using a lipophilic Laurdan dye and confocal fluorescence microscopy, we observed cell membrane perturbation and actin reorganization induced by Aß oligomers but not by Aß monomers or amyloid fibrils. We further revealed recovery of membrane fluidity by ultrasmall MoS2 quantum dots, also shown in this study as a potent inhibitor of Aß amyloid aggregation. Using discrete molecular dynamics simulations, we uncovered the binding of MoS2 and Aß monomers as mediated by hydrophilic interactions between the quantum dots and the peptide N-terminus. In contrast, Aß 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 the cell membrane and adverse effects downstream. This study offers a crucial new insight and a viable strategy for regulating the amyloid aggregation and membrane-axis of AD pathology with multifunctional nanomedicine.

Spontaneous Formation of ß-sheet Nano-barrels during the Early Aggregation of Alzheimer's Amyloid Beta.

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 Aß42 oligomers. Aß peptides readily assembled into ß-rich oligomers comprised of extended ß-hairpins and ß-strands. Nanosized ß-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 ß-sheet propensities and inter-residue contact frequency patterns, were similar to the properties known for Aß fibrils. The unambiguous spontaneous formation of ß-barrels in the early aggregation of Aß42 supports their roles as the common toxic intermediates in Alzheimer's pathobiology and a target for Alzheimer's therapeutics.

The membrane axis of Alzheimer's nanomedicine.

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 (Aß) 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, here we summarize the membrane axis of AD nanomedicine and present a new rationale that the field development may greatly benefit from harnessing our existing knowledge of Aß-membrane interaction, nanoparticle-membrane interaction and Aß-nanoparticle interaction.

In vitro and in vivo models for anti-amyloidosis nanomedicines.

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 ß2-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).

Nanotoxicology and Nanomedicine: The Yin and Yang of Nano-Bio Interactions for the New Decade.

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.

Amyloid Aggregation under the Lens of Liquid-Liquid Phase Separation.

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.

Human Plasma Protein Corona of Aß 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-ß (Aß) 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 Aß amyloid or oligomers, largely to no avail. Aß 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 Aß-Aß1-42 and Aß1-40-exposed to human blood plasma. Out of the proteins identified in all groups, 58 proteins were unique to the Aß1-42 samples and 31 proteins unique to the Aß1-40 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 Aß1-42 fibrils by their structurally specific antibodies and accelerated the aggregation but not the ß-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.

Mitigation of Amyloidosis with Nanomaterials.

Amyloidosis is a biophysical phenomenon of protein aggregation with biological and pathogenic implications. Among the various strategies developed to date, nanomaterials and multifunctional nanocomposites possessing certain structural and physicochemical traits are promising candidates for mitigating amyloidosis in vitro and in vivo. The mechanisms underpinning protein aggregation and toxicity are introduced, and opportunities in materials science to drive this interdisciplinary field forward are highlighted. Advancement of this emerging frontier hinges on exploitation of protein self-assembly and interactions of amyloid proteins with nanoparticles, intracellular and extracellular proteins, chaperones, membranes, organelles, and biometals.

Graphene quantum dots rescue protein dysregulation of pancreatic ß-cells exposed to human islet amyloid polypeptide.

The amyloid aggregation of peptides and proteins is a hallmark of neurological disorders and type 2 diabetes. Human islet amyloid polypeptide (IAPP), co-secreted with insulin by pancreatic ß-cells, plays dual roles in both glycemic control and the pathology of type 2 diabetes. While IAPP can activate the NLRP3 inflammasome and modulate cellular autophagy, apoptosis and extracellular matrix metabolism, no data is available concerning intracellular protein expression upon exposure to the polypeptide. More surprisingly, how intracellular protein expression is modulated by nanoparticle inhibitors of protein aggregation remains entirely unknown. In this study, we first examined the changing proteomes of ßTC6, a pancreatic ß-cell line, upon exposure to monomeric, oligomeric and fibrillar IAPP, and detailed cellular protein expression rescued by graphene quantum dots (GQDs), an IAPP inhibitor. We found that 29 proteins were significantly dysregulated by the IAPP species, while majority of these proteins were nucleotide-binding proteins. Collectively, our liquid chromatography tandem-mass spectrometry, fluorescence quenching, helium ion microscopy, cytotoxicity and discreet molecular dynamics simulations data revealed a remarkable capacity of GQDs in regulating aberrant protein expression through H-bonding and hydrophobic interactions, pointing to nanomedicine as a new frontier against human amyloid diseases.

Inhibition of amyloid beta toxicity in zebrafish with a chaperone-gold nanoparticle dual strategy.

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders, yet no major breakthroughs have been made in AD human trials and the disease remains a paramount challenge and a stigma in medicine. Here we eliminate the toxicity of amyloid beta (Aß) in a facile, high-throughput zebrafish (Danio rerio) model using casein coated-gold nanoparticles (ßCas AuNPs). ßCas AuNPs in systemic circulation translocate across the blood brain barrier of zebrafish larvae and sequester intracerebral Aß42 and its elicited toxicity in a nonspecific, chaperone-like manner. This is evidenced by behavioral pathology, reactive oxygen species and neuronal dysfunction biomarkers assays, complemented by brain histology and inductively coupled plasma-mass spectroscopy. We further demonstrate the capacity of ßCas AuNPs in recovering the mobility and cognitive function of adult zebrafish exposed to Aß. This potent, safe-to-use, and easy-to-apply nanomedicine may find broad use for eradicating toxic amyloid proteins implicated in a range of human diseases.

Single-Molecular Heteroamyloidosis of Human Islet Amyloid Polypeptide.

Human amyloids and plaques uncovered post mortem are highly heterogeneous in structure and composition, yet literature concerning the heteroaggregation of amyloid proteins is extremely scarce. This knowledge deficiency is further exacerbated by the fact that peptide delivery is a major therapeutic strategy for targeting their full-length counterparts associated with the pathologies of a range of human diseases, including dementia and type 2 diabetes (T2D). Accordingly, here we examined the coaggregation of full-length human islet amyloid polypeptide (IAPP), a peptide associated with type 2 diabetes, with its primary and secondary amyloidogenic fragments 19-29 S20G and 8-20. Single-molecular aggregation dynamics was obtained by high-speed atomic force microscopy, augmented by transmission electron microscopy, X-ray diffraction, and super-resolution stimulated emission depletion microscopy. The coaggregation significantly prolonged the pause phase of fibril elongation, increasing its dwell time by 3-fold. Surprisingly, unidirectional elongation of mature fibrils, instead of protofilaments, was observed for the coaggregation, indicating a new form of tertiary protein aggregation unknown to existing theoretical models. Further in vivo zebrafish embryonic assay indicated improved survival and hatching, as well as decreased frequency and severity of developmental abnormalities for embryos treated with the heteroaggregates of IAPP with 19-29 S20G, but not with 8-20, compared to the control, indicating the therapeutic potential of 19-29 S20G against T2D.

Amphiphilic surface chemistry of fullerenols is necessary for inhibiting the amyloid aggregation of alpha-synuclein NACore.

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-ß 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-ß aggregates via intermediates including ß-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 ß-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 ß-sheets between peptides adsorbed onto the surfaces of fullerenols or fullerenol nano-assemblies due to hydrophobic interactions. Thus, both cross-ß aggregates and ß-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.