Engineering Core/Ligands Interfacial Anchors of Nanoparticles for Efficiently Inhibiting Both Aß and Amylin Fibrillization.

Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aß and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aß40 fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.

Charge Effect of Mercaptobenzimidazole-Modified Ultrasmall Gold-Nanoparticles against Drug-Resistant Bacteria.

The threat of bacterial infections, especially drug-resistant strains, to human health necessitates the development of high-efficient, broad-spectrum and nonantibiotic nanodisinfectant. However, the effect of interfacial charge on the antibacterial properties of nanodisinfectant remains a mystery, which greatly limits the development of highly antibacterial active nanodisinfectant. Herein, we developed three types of ultrasmall (d < 3 nm) gold-nanoparticles (AuNPs) modified with 5-carboxylic(C)/methoxy(M)amino(A)/-2-mercaptobenzimidazole (C/M/A MB) to investigate their interfacial charge on antibacterial performance. Our results showed that both the electropositive AMB-AuNPs and electronegative CMB-AuNPs exhibited no antibacterial activity against both Gram-positive (G+) and Gram-negative (G-) bacteria. However, the electroneutral MMB-AuNPs exhibited unique antibacterial performance against both G+ and G- bacteria, even against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic investigation revealed a multipathway synergistic bacteriostatic mechanism involving MMB-AuNPs inducing damage to bacterial cell membranes, disruption of membrane potential and downregulation of ATP levels, ultimately leading to bacterial demise. Furthermore, two additional electroneutral AuNPs modified with 5-methyl-2-mercaptobenzimidazole (mMB-AuNPs) and 5-ethoxy-2-mercaptobenzimidazole (EMB-AuNPs) also demonstrated commendable antibacterial efficacy against E. coli, S. aureus, and MRSA; however, their performance was comparatively inferior to that of MMB-AuNPs. This work provides valuable insights for the development of high-performance antibacterial nanomaterials.

Palladium-Catalyzed Domino Heck/Cross-Coupling Cyclization Reaction: Diastereoselective Synthesis of Furan-Containing Indolines.

Herein, a palladium-catalyzed diastereoselective dearomatization/cross-coupling cyclization reaction between N-arylacyl indoles and (E)-ß-chlorovinyl ketones is reported. Through this cyclization/cycloisomerization cascade, a series of furan-containing indolines were obtained in yields up to 95%. The reaction features readily accessible starting materials, benzyl Pd(II)-catalyzed cycloisomerization of (E)-ß-chlorovinyl ketones, the sequential formation of three bonds and bis-heterocycles, and excellent diastereoselectivity. More importantly, the carbene-secondary benzyl migratory insertion is proven to be a critical process in the sequential cyclizations.

SM protein Sly1 and a SNARE Habc domain promote membrane fusion through multiple mechanisms.

SM proteins including Sly1 are essential cofactors of SNARE-mediated membrane fusion. Using SNARE and Sly1 mutants and chemically defined in vitro assays, we separate and assess proposed mechanisms through which Sly1 augments fusion: (i) opening the closed conformation of the Qa-SNARE Sed5; (ii) close-range tethering of vesicles to target organelles, mediated by the Sly1-specific regulatory loop; and (iii) nucleation of productive trans-SNARE complexes. We show that all three mechanisms are important and operate in parallel, and that close-range tethering promotes trans-complex assembly when cis-SNARE assembly is a competing process. Further, we demonstrate that the autoinhibitory N-terminal Habc domain of Sed5 has at least two positive activities: it is needed for correct Sed5 localization, and it directly promotes Sly1-dependent fusion. "Split Sed5," with Habc presented solely as a soluble fragment, can function both in vitro and in vivo. Habc appears to facilitate events leading to lipid mixing rather than promoting opening or stability of the fusion pore.

Flexibility Analysis of DNA Nanotubes with Prescribed Circumferences and Their Pearl-Necklace Assemblies with Gold Nanoclusters.

DNA has been demonstrated as a powerful platform for the construction of inorganic nanoparticles (NPs) into complex three-dimensional assemblies. Despite extensive research, the physical fundamental details of DNA nanostructures and their assemblies with NPs remain obscure. Here, we report the identification and quantification of the assembly details of programmable DNA nanotubes with monodisperse circumferences of a 4, 5, 6, 7, 8, or 10 DNA helix and their pearl-necklace-like assemblies with ultrasmall gold nanoparticles, Au25 nanoclusters (AuNCs), liganded by -S(CH2)nNH3+ (n = 3, 6, 11). The flexibilities of DNA nanotubes, analyzed via statistical polymer physics analysis through atomic force microscopy (AFM), demonstrate that ∼2.8 power exponentially increased with the DNA helix number. Moreover, the short-length liganded AuS(CH2)3NH3+ NCs were observed to be able to form pearl-necklace-like DNA-AuNC assemblies stiffened than neat DNA nanotubes, while long-length liganded AuS(CH2)6NH3+ and AuS(CH2)11NH3+ NCs could fragment DNA nanotubular structures, indicating that DNA-AuNC assembling can be precisely manipulated by customizing the hydrophobic domains of the AuNC nanointerfaces. We prove the advantages of polymer science concepts in unraveling useful intrinsic information on physical fundamental details of DNA-AuNC assembling, which facilitates DNA-metal nanocomposite construction.

Distributed Consensus Kalman Filter Design with Dual Energy-Saving Strategy: Event-Triggered Schedule and Topological Transformation.

In the distributed information fusion of wireless sensor networks (WSNs), the filtering accuracy is commonly negatively correlated with energy consumption. Therefore, a class of distributed consensus Kalman filters was designed to balance the contradiction between them in this paper. Firstly, an event-triggered schedule was designed based on historical data within a timeliness window. Furthermore, considering the relationship between energy consumption and communication distance, a topological transformation schedule with energy-saving is proposed. The energy-saving distributed consensus Kalman filter with a dual event-driven (or event-triggered) strategy is proposed by combining the above two schedules. The sufficient condition of stability for the filter is given by the second Lyapunov stability theory. Finally, the effectiveness of the proposed filter was verified by a simulation.

Modeling and Parameter Identification of a 3D Measurement System Based on Redundant Laser Range Sensors for Industrial Robots.

The low absolute positioning accuracy of industrial robots is one of the bottlenecks preventing industrial robots from precision applications. Kinematic calibration is the main way to improve the absolute positioning accuracy of industrial robots, which greatly relies on three-dimensional (3D) measurement instruments, including laser trackers and pull rope mechanisms. These instruments are costly, and their required intervisibility space is large. In this paper, a precision 3D measurement instrument integrating multiple laser range sensors is designed, which fuses the information of multiple redundant laser range sensors to obtain the coordinates of a 3D position. An identification model of laser beam position and orientation parameters based on redundant distance information and standard spherical constraint is then developed to reduce the requirement for the assembly accuracy of laser range sensors. A hybrid identification algorithm of PSO-LM (particle swarm optimization Levenberg Marquardt) is designed to solve the high-order nonlinear problem of the identification model, where PSO is used for initial value identification, and LM is used for final value identification. Experiments of identification of position and orientation, verifications of the measuring accuracy, and the calibration of industrial robots are conducted, which show the effectiveness of the proposed 3D measurement instrument and identification methods. Moreover, the proposed instrument is small in size and can be used in narrow industrial sites.

Gold Nanoclusters Enhance the Efficacy of the Polymer-Based Chaperone in Restoring and Maintaining the Native Conformation of Human Islet Amyloid Polypeptide.

The misfolding and un-natural fibrillation of proteins/peptides are associated with many conformation diseases, such as human islet amyloid polypeptide (hIAPP) in type 2 diabetes (T2D). Inspired by molecular chaperones maintaining protein homeostasis in vivo, many polymer-based artificial chaperones were introduced to regulate protein/peptide folding and fibrillation. However, the pure polymer chaperones prefer to agglomerate into large-size micelles in the physiological environment and thus lose their chaperone functions, which greatly restricts the application of polymer-based chaperones. Here, we designed and prepared a core-shell artificial chaperone based on a dozen poly-(N-isopropylacrylamide-co-N-acryloyl-O-methylated-l-arginine) (PNAMR) anchored on a gold-nanocluster (AuNC) core. The introduction of the AuNC core significantly reduced the size and enhanced the efficacy and stability of polymer-based artificial chaperones. The PNAMR@AuNCs, with a diameter of 2.5 ± 0.5 nm, demonstrated exceptional ability in maintaining the natively unfolded conformation of protein away from the misfolding and the following fibrillation by directly binding to the natively unfolded monomolecular hIAPP and hence in preventing their conversion into toxic oligomers. More excitingly, the PNAMR@AuNCs were able to restore the natural unfolded conformation of hIAPP via dissolving the ß-sheet-rich hIAPP fibrils. Considering the uniform molecular mechanism of protein misfolding and fibrillation in conformation disorders, this finding provides a generic therapeutic strategy for neurodegenerative diseases and other conformation diseases by using PNAMR@AuNC artificial chaperones to restore and maintain the native conformation of amyloid proteins.

The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review.

Schizophrenia (SCZ) is a serious mental illness that affects 1% of people worldwide. SCZ is associated with a higher risk of developing metabolic disorders such as obesity. Antipsychotics are the main treatment for SCZ, but their side effects include significant weight gain/obesity. Despite extensive research, the underlying mechanisms by which SCZ and antipsychotic treatment induce weight gain/obesity remain unclear. Hypothalamic endoplasmic reticulum (ER) stress is one of the most important pathways that modulates inflammation, neuronal function, and energy balance. This review aimed to investigate the role of hypothalamic ER stress in SCZ and antipsychotic-induced weight gain/obesity. Preliminary evidence indicates that SCZ is associated with reduced dopamine D2 receptor (DRD2) signaling, which significantly regulates the ER stress pathway, suggesting the importance of ER stress in SCZ and its related metabolic disorders. Antipsychotics such as olanzapine activate ER stress in hypothalamic neurons. These effects may induce decreased proopiomelanocortin (POMC) processing, increased neuropeptide Y (NPY) and agouti-related protein (AgRP) expression, autophagy, and leptin and insulin resistance, resulting in hyperphagia, decreased energy expenditure, and central inflammation, thereby causing weight gain. By activating ER stress, antipsychotics such as olanzapine activate hypothalamic astrocytes and Toll-like receptor 4 signaling, thereby causing inflammation and weight gain/obesity. Moreover, evidence suggests that antipsychotic-induced ER stress may be related to their antagonistic effects on neurotransmitter receptors such as DRD2 and the histamine H1 receptor. Taken together, ER stress inhibitors could be a potential effective intervention against SCZ and antipsychotic-induced weight gain and inflammation.

Advances of gold nanoclusters for bioimaging.

Gold nanoclusters (AuNCs) have become a promising material for bioimaging detection because of their tunable photoluminescence, large Stokes shift, low photobleaching, and good biocompatibility. Last decade, great efforts have been made to develop AuNCs for enhanced imaging contrast and multimodal imaging. Herein, an updated overview of recent advances in AuNCs was present for visible fluorescence (FL) imaging, near-infrared fluorescence (NIR-FL) imaging, two-photon near-infrared fluorescence (TP-NIR-FL) imaging, computed tomography (CT) imaging, positron emission tomography (PET) imaging, magnetic resonance imaging (MRI), and photoacoustic (PA) imaging. The justification of AuNCs applied in bioimaging mentioned above applications was discussed, the performance location of different AuNCs were summarized and highlighted in an unified parameter coordinate system of corresponding bioimaging, and the current challenges, research frontiers, and prospects of AuNCs in bioimaging were discussed. This review will bring new insights into the future development of AuNCs in bio-diagnostic imaging.

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist.

Emerging data indicate that antipsychotic treatment causes brain volume loss and astrocyte death, but the mechanisms remain elusive. Pyroptosis, inflammatory cell death characterized by the formation of inflammatory bodies, increased expression of nod-like receptor proteins (NLRPs) such as NLRP3, and activation of caspases and gasdermin D (GSDMD) are largely associated with innate immunity, inflammation, and cell injury/death. However, the main effect of antipsychotics on astrocyte pyroptotic signaling and the molecular mechanisms remain obscure. In the present study, 72-h treatment with olanzapine, quetiapine, risperidone, or haloperidol significantly decreased the viability of astrocytes. Twenty-four hour treatment with olanzapine, quetiapine, risperidone, or haloperidol dose-dependently increased the protein expression of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-treatment with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), dose-dependently reduced the increased expression of NLRP3, caspase-1 and GSDMD induced by olanzapine, quetiapine, risperidone, or haloperidol. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment induced pore formation in the membranes of astrocytes, and these effects were inhibited by FMPH co-treatment. Taken together, antipsychotic treatment activated astrocyte pyroptotic signaling, and these effects may be related to antipsychotic-induced astrocyte death. H1 receptor activation is an effective treatment strategy to suppress antipsychotic-induced astrocyte pyroptosis and inflammation.

High efficiency and related mechanism of Au(RC) nanoclusters on disaggregating Aß fibrils.

Revealing the disaggregating mechanism of amyloids fibrils under nanomaterials action is a key issue for their successful future use in therapy of neurodegenerative and overall amyloid-related diseases. Herein a gold nanocluster stabilized by Arg-Cys dipeptide (Au(RC)NCs) was synthesized to investigate its disaggregation activity toward Aß fibrils by using Thioflavin-T (ThT) fluorescence assay and atomic force microscopy. It was demonstrated that Au(RC)NCs is very effective in disaggregating preformed Aß fibrils, and characterized by the ultra-low apparent completely disaggregation concentration at the dose of 10 µg·mL-1. A possible disaggregation mechanism based on Au(RC)NCs triggering the disassembly of Aß fibrils into a dynamic equilibrium was proposed. The introduction of Au(RC)NCs with appropriate dose (5 µg·mL-1) can trigger the disassemble process of mature Aß fibrils into a critical state, at this very moment, if there is no more nano-disassembler, destruction of old Aß fibrils and formation of new Aß fibrils are thus in permanent dynamic equilibrium; in contrast, if there is more nano-disassembler (>10 µg·mL-1), the dynamic equilibrium prefer to shift to the direction of Aß further disassembly. Moreover, Au(RC)NCs with dosage over 10 µg·mL-1 exhibited superb protection effect against Aß-induced cytotoxicity in cell experiments. This study not only proposed a possible disassembly mechanism of amyloids fibrils under nanomaterials action, but also provide Au(RC)NCs as a promising high-effective nano-disassembler to disassemble unwanted amyloid aggregates.

Gold nanoclusters eliminate obesity induced by antipsychotics.

Obesity induced by antipsychotics have plagued more than 20 million people worldwide. However, no drug is available to eliminate the obesity induced by antipsychotics. Here we examined the effect and potential mechanisms of a gold nanoclusters (AuNCs) modified by N-isobutyryl-L-cysteine on the obesity induced by olanzapine, the most prescribed but obesogenic antipsychotics, in a rat model. Our results showed that AuNCs completely prevented and reversed the obesity induced by olanzapine and improved glucose metabolism profile in rats. Further mechanism investigations revealed that AuNCs exert its anti-obesity function through inhibition of olanzapine-induced dysfunction of histamine H1 receptor and proopiomelanocortin signaling therefore reducing hyperphagia, and reversing olanzapine-induced inhibition of uncoupling-protein-1 signaling which increases thermogenesis. Together with AuNCs' good biocompatibility, these findings not only provide AuNCs as a promising nanodrug candidate for treating obesity induced by antipsychotics, but also open an avenue for the potential application of AuNCs-based nanodrugs in treating general obesity.

Engineering Nanointerfaces of Au25 Clusters for Chaperone-Mediated Peptide Amyloidosis.

Synthetic nanomaterials possessing biomolecular-chaperone functions are good candidates for modulating physicochemical interactions in many bioapplications. Despite extensive research, no general principle to engineer nanomaterial surfaces is available to precisely manipulate biomolecular conformations and behaviors, greatly limiting attempts to develop high-performance nanochaperone materials. Here, we demonstrate that, by quantifying the length (-SCxR±, x = 3-11) and charges (R- = -COO-, R+ = -NH3+) of ligands on Au25 gold nanochaperones (AuNCs), simulating binding sites and affinities of amyloid-like peptides with AuNCs, and probing peptide folding and fibrillation in the presence of AuNCs, it is possible to precisely manipulate the peptides' conformations and, thus, their amyloidosis via customizing AuNCs nanointerfaces. We show that intermediate-length liganded AuNCs with a specific charge chaperone peptides' native conformations and thus inhibit their fibrillation, while other types of AuNCs destabilize peptides and promote their fibrillation. We offer a microscopic molecular insight into peptide identity on AuNCs and provide a guideline in customizing nanochaperones via manipulating their nanointerfaces.

Unknown System Dynamics Estimator for Active Vehicle Suspension Control Systems With Time-Varying Delay.

This article proposes a novel control method for vehicle active suspension systems in the presence of time-varying input delay and unknown nonlinearities. An unknown system dynamics estimator (USDE), which employs first-order low-pass filter operations and has only one tuning parameter, is constructed to deal with unknown nonlinearities. With this USDE, the widely used function approximators (e.g., neural networks and fuzzy-logic systems) are not needed, and the intermediate variables and observer used in the traditional estimators are not required. This estimator has a reduced computational burden, trivial parameter tuning and guaranteed convergence. Moreover, a predictor-based compensation strategy is developed to handle the time-varying input delay. Finally, we combine the suggested USDE and predictor to design a feedback controller to attenuate the vibrations of vehicle body and retain the required suspension performances. Theoretical analysis is carried out via the Lyapunov-Krasovkii functional to prove the stability of the closed-loop system. Simulation results based on professional vehicle simulation software Carsim are provided to show the efficiency of the proposed control scheme.

Isomeric Effect of Nano-Inhibitors on Aß40 Fibrillation at The Nano-Bio Interface.

Chemical and physical properties of nanobio interface substantially affect the conformational transitions of adjacent biomolecules. Previous studies have reported the chiral effect and charge effect of nanobio interface on the misfolding, aggregation, and fibrillation of amyloid protein. However, the isomeric effect of nanobio interface on protein/peptides amyloidosis is still unclear. Here, three isomeric nanobio interfaces were designed and fabricated based on the same sized gold nanoclusters (AuNCs) modified with 4-mercaptobenzoic acid (p-MBA), 3-mercaptobenzoic acid (m-MBA), and 2-mercaptobenzoic acid (o-MBA). Then three isomeric AuNCs were employed as models to explore the isomeric effect on the misfolding, aggregation, and fibrillation of Aß40 at nanobio interfaces. Site-specific replacement experiments on the basis of theoretical analysis revealed the possible mechanism of Aß40 interacting with isomeric ligands of AuNCs at the nanobio interfaces. The distance and orientation of -COOH group from the surface of AuNCs can affect the electrostatic interaction between isomeric ligands and the positively charged residues (R5, K16, and K28) of Aß40, which may affect the inhibition efficiency of isomeric AuNCs on protein amyloidosis. Actually, the amyloid fibrillation kinetics results together with atomic force microscope (AFM) images, dynamic light scattering (DLS) results and circular dichroism (CD) spectra indeed proved that all the three isomeric AuNCs could inhibit the misfolding, aggregation and fibrillation of Aß40 in a dose-dependent manner, and the inhibition efficiency was definitely different from each other. The inhibition efficiency of o-MBA-AuNCs was higher than that of m-MBA-AuNCs and p-MBA-AuNCs at the same dosage. These results provide an insight for isomeric effect at nanobio interfaces, and open an avenue for structure-based nanodrug design target Alzheimer's disease (AD) and even other protein conformational diseases.

Output-Feedback Robust Control of Uncertain Systems via Online Data-Driven Learning.

Although robust control has been studied for decades, the output-feedback robust control design is still challenging in the control field. This article proposes a new approach to address the output-feedback robust control for continuous-time uncertain systems. First, we transform the robust control problem into an optimal control problem of the nominal linear system with a constructive cost function, which allows simplifying the control design. Then, a modified algebraic Riccati equation (MARE) is constructed by further investigating the corresponding relationship with the state-feedback optimal control. To solve the derived MARE online, the vectorization operation and Kronecker's product are applied to reformulate the output Lyapunov function, and then, a new online data-driven learning method is suggested to learn its solution. Consequently, only the measurable system input and output are used to derive the solution of the MARE. In this case, the output-feedback robust control gain can be obtained without using the unknown system states. The control system stability and convergence of the derived solution are rigorously proved. Two simulation examples are provided to demonstrate the efficacy of the suggested methods.

Charge effects at nano-bio interfaces: a model of charged gold nanoclusters on amylin fibrillation.

The misfolding and abnormal amyloid fibrillation of proteins/peptides are associated with more than 20 human diseases. Although dozens of nanoparticles have been investigated for the inhibition effect on the misfolding and fibrillation of pathogenesis-related proteins/peptides, there are few reports on charge effects of nano inhibitors on amyloid fibrillation. Herein, same-sized gold nanoclusters modified with 2-aminoethanethiol hydrochloride (CSH-AuNCs, positively charged in pH 7.4) or 3-mercaptopropionic acid (MPA-AuNCs, negatively charged in pH 7.4) were synthesized and adopted as models to explore the charge effect of nano inhibitors on amylin fibrillation at the nano-bio interface. ThT fluorescence kinetics analysis, AFM images and circular dichroism (CD) spectra showed that electropositive CSH-AuNCs inhibited the misfolding and fibrillation of amylin in a dosage-dependent manner, but electronegative MPA-AuNCs accelerated the misfolding and fibrillation of amylin in a dosage-dependent manner. Moreover, the theoretical and experimental results revealed the interaction mechanism between amylin and ligands of AuNCs at the nano-bio interfaces. Electropositive CSH-AuNCs could be bound to the main nucleating region of amylin via hydrogen bonding and endowed the nanocomplex with more positive net charges (amylin monomer with a positive +26.23 ± 0.80 mV zeta potential), which would inhibit the misfolding and aggregation of amylin via electrostatic repulsion and steric hindrance. In contrast, electronegative MPA-AuNCs could absorb electropositive amylin via strong electrostatic attractions, which accelerated the fibrillation process of amylin via enhancing local concentrations. Moreover, cell experiments showed that both the charged AuNCs had good biocompatibility and electronegetive MPA-AuNCs showed a better protective effect in the amylin-induced cell model than electropositive CSH-AuNCs. These results provide an insight into structure-based nanodrug design for protein conformational diseases.

Optimal route of gold nanoclusters administration in mice targeting Parkinson's disease.

Aim: To explore the optimal route of gold nanoclusters (AuNCs) administration in mice targeting Parkinson's disease. Materials & methods: Assessing the pharmacokinetic and bioavailability of AuNCs in mice administrated following intravenous, intraperitoneal, gavage and intranasal injection. Investigating the biodistribution of AuNCs in mice by atomic absorption spectrometry and transmission electron microscope. Toxicity assessments of AuNCs were carried out both in cells and in mice. Results: Administration of AuNCs via intraperitoneal injection showed the greatest bioavailability and the longest residence in brain. AuNCs could penetrate blood-brain barrier and be excreted mainly through kidney. No obvious toxicity of AuNCs found in cells and in mice. Conclusion: The optimal route of AuNCs administration in mice targeting Parkinson's disease is intraperitoneal administration.

Au23(CR)14 nanocluster restores fibril Aß's unfolded state with abolished cytotoxicity and dissolves endogenous Aß plaques.

The misfolding of amyloid-ß (Aß) peptides from the natural unfolded state to ß-sheet structure is a critical step, leading to abnormal fibrillation and formation of endogenous Aß plaques in Alzheimer's disease (AD). Previous studies have reported inhibition of Aß fibrillation or disassembly of exogenous Aß fibrils in vitro. However, soluble Aß oligomers have been reported with increased cytotoxicity; this might partly explain why current clinical trials targeting disassembly of Aß fibrils by anti-Aß antibodies have failed so far. Here we show that Au23(CR)14 (a new Au nanocluster modified by Cys-Arg (CR) dipeptide) is able to completely dissolve exogenous mature Aß fibrils into monomers and restore the natural unfolded state of Aß peptides from misfolded ß-sheets. Furthermore, the cytotoxicity of Aß40 fibrils when dissolved by Au23(CR)14 is fully abolished. More importantly, Au23(CR)14 is able to completely dissolve endogenous Aß plaques in brain slices from transgenic AD model mice. In addition, Au23(CR)14 has good biocompatibility and infiltration ability across the blood-brain barrier. Taken together, this work presents a promising therapeutics candidate for AD treatment, and manifests the potential of nanotechnological approaches in the development of nanomedicines.