Advanced nanomaterials for modulating Alzheimer's related amyloid aggregation

Alzheimer's disease (AD) is a common neurodegenerative disease that brings about enormous economic pressure to families and society. Inhibiting abnormal aggregation of Aβ and accelerating the dissociation of aggregates is treated as an effective method to prevent and treat AD. Recently, nanomaterials have been applied in AD treatment due to their excellent physicochemical properties and drug activity. As a drug delivery platform or inhibitor, various excellent nanomaterials have exhibited potential in inhibiting Aβ fibrillation, disaggregating, and clearing mature amyloid plaques by enhancing the performance of drugs. This review comprehensively summarizes the advantages and disadvantages of nanomaterials in modulating amyloid aggregation and AD treatment. The design of various functional nanomaterials is discussed, and the strategies for improved properties toward AD treatment are analyzed. Finally, the challenges faced by nanomaterials with different dimensions in AD-related amyloid aggregate modulation are expounded, and the prospects of nanomaterials are proposed.


Introduction
Protein misfolding can form abnormal amyloid aggregates, further leading to amyloid extracellular deposition. 1 These amyloid deposits are widely believed to be closely related to various neurodegenerative diseases and are even considered to be the culprit. 2 Among them, Alzheimer's disease (AD) is the most common form of neurodegenerative disease, and according to the "2021 World Alzheimer's Disease Report", more than 55 million people worldwide have dementia. This number gets even more staggering as it grows daily and is expected to reach 78 million by 2030. 3 Although the pathogenesis of AD has not been clearly conrmed, the amyloid plaque hypothesis has been the most widely accepted until now. 4 As the most important component of amyloid aggregates, Ab is derived from the sequential proteolytic cleavage of b-amyloid precursor protein (APP) by band g-secretase in vivo. 5 In addition, Ab is a hydrophobic peptide with a molecular weight of 4 kDa and consists of 39-42 amino acid residues. 5,6 The Ab monomer undergoes secondary structural transitions and misfolds in physiological environments. 7 This misfolding Ab can rapidly self-assemble with surrounding Ab and form oligomers through hydrophobic interactions. Meanwhile, the oligomers can then decrease through the conversion of non-brillar to brillar oligomers, elongating brillar oligomers and nally forming mature amyloid brils. 8 The process of Ab aggregation can trigger the production of intra-and extra-cellular reactive oxygen species (ROS), which can lead to oxidation and cellular damage. 9 In addition, neurotoxicity was induced by Ab oligomers and brils through binding to the plasma membrane, resulting in metabolic dysfunction and neuronal cell death. 10 Therefore, the inhibition of Ab brillation, the disintegration of mature Ab aggregates, and the promotion of the clearance of Ab to maintain the balance of the metabolism and catabolism of Ab appear to be quite signicant for the prevention and treatment of AD. Recently, numerous efforts have been made to inhibit Ab aggregation by blocking bril formation and reducing the number of brils to halt the extent of AD pathology. [10][11][12] Among them, nanomaterials have great advantages in inuencing amyloid bril nucleation, disintegrating matured amyloid brils, and targeting amyloid plaques via crossing the blood-brain barrier (BBB). 10,[13][14][15][16] At the same time, nanomaterials have an ability to respond to light, sound, heat, electricity, and magnetism because of the physical properties of some nanomaterials, and they have also been gradually developed and applied in the research of neurodegenerative diseases. 10,[17][18][19][20][21] Nanomaterials can be classied into one-dimensional, twodimensional, zero-dimensional, and other nanomaterials according to their dimensions. 22 One-dimensional nanomaterials exhibit a high degree of anisotropy, possessing excellent properties such as plasmon resonance, optical properties and antioxidation. 23 Two-dimensional nanomaterials have excellent physical and chemical properties, can bind peptides through non-covalent forces, have good biocompatibility, and have good photothermal conversion and photocatalytic capabilities. [24][25][26] The large specic surface area of zero-dimensional nanomaterials makes them have unique physical and chemical properties. 27 Besides, some composite nanomaterials prepared from other nanocarriers, such as metal-organic frameworks, polyoxometalates, and silica, have multiple synergistic effects. [28][29][30] Based on the three-dimensional scale of nanomaterials, this review deeply analyzed the advantages/disadvantages of nanomaterials in modulating amyloid aggregation. The modulation roles of nanomaterials in AD treatment mainly include intermolecular interaction, chelation, photothermal effects, photocatalytic oxidation, and drug delivery (Fig. 1A). As shown in Fig. 1B, we exhibited a number of research articles published each year on the application of nanomaterials in amyloid, neurodegenerative disease (ND), and Alzheimer's disease (AD). This exponential growth of research in the related eld indicates that nanomaterials for modulating Alzheimer's related amyloid aggregation are not only an emerging research topic, but also possess huge application potential.

One-dimensional nanomaterials
One-dimensional (1D) nanomaterials, including nanorods, nanotubes, nanoribbons, nanowires, and nanobers, have been applied as drug carrier or synergistic drug materials. 31,32 Due to their unique chemical structures, good biocompatibility, high specic surface area, and other related physicochemical properties, 1D nanomaterials were widely applied to the biological eld. 33 In recent years, some research showed that 1D nanomaterials with special structures, such as radial size seamless carbon tubes, can interact with amyloid protein and reduce the aggregation of amyloid protein. 34

Carbon nanotubes
Carbon nanotubes with a special structure fabricated from graphene sheets are one-dimensional quantum materials. 35 It is mainly composed of several to dozens of layers of coaxial circular tubes of carbon atoms arranged in a hexagonal shape. 36 A xed distance of about 0.34 nm is maintained between layers, and the diameter of nanotubes is generally 2-20 nm. 37 According to the different orientations of the hexagon along the axial direction, it can be divided into zigzag, armchair and spiral. 38 Single-walled carbon nanotubes (SWCNTs) have been applied in various biological systems because of their good biocompatibility, unique chemical structure, high specic surface area and strong optical absorbance in the near-infrared (NIR) region. 39 As unique one-dimensional nanomaterials, SWCNTs have also been explored as novel delivery vehicles for drugs, proteins, and so on. 40,41 Due to the strong optical absorbance of SWCNTs in the NIR region, SWCNTs could destroy the structure of cells by local thermal during NIR laser irradiation. 42 As a nanocarrier, SWCNTs were used to deliver oligonucleotides into living cells, and oligos were translocated into cell nuclei upon endosomal rupture triggered by NIR laser pulses. 43,44 It can be seen that the transporting capabilities of SWCNTs combined with chemical modication and their intrinsic optical properties can lead to new classes of novel nanomedicine for drug delivery and therapy. To the best of our knowledge, SWCNTs have also been developed for inhibiting amyloid brillation, disintegration of amyloid brils, and promoting the clearance of amyloid plaques. Luo et al. 45 rstly studied the pH-dependent molecular interactions between SWCNTs and Ab peptides by a variety of spectroscopy and atomic force microscopy techniques. They found that the secondary structural transition of Ab peptides from a random coil to a b-sheet structure could be signicantly affected by SWCNTs, and SWCNTs could inhibit the nucleation/ elongation phase of Ab peptide brillation by adsorbing Ab peptides with a b-sheet structure ( Fig. 2A). Their research also indicated that Ab peptides might reduce the toxicity of SWCNTs by the reduction of the hydrophobic surface of SWCNTs. Wei's group 46 showed that SWCNTs could inhibit the formation of bsheet-rich oligomers in the central hydrophobic core fragment of Ab (Ab [16][17][18][19][20][21][22] ). However, a potential problem with SWCNTs is their poor solubility in water and few functional groups, which will cause a huge hindrance to the inhibition of Ab brillation and other biological applications. Therefore, Xie et al. 47 fabricated a type of hydroxylated SWCNTs by modifying with 30 hydroxyl groups. Then they further investigated the inuence of hydroxylated SWCNTs on the aggregation of Ab [16][17][18][19][20][21][22] peptides using all-atom explicit-water replica exchange molecular dynamics simulations. The results showed that the b-sheet formation, shi in the conformations and disordered aggregation of Ab [16][17][18][19][20][21][22] peptides can be signicantly inhibited through hydroxylated SWCNTs, which mainly depend on the strong electrostatic, hydrophobic, and aromatic stacking interactions with the residue of Ab [16][17][18][19][20][21][22] . In addition, Liu et al. 48 also researched the ability of hydroxylated SWCNTs for inhibiting Ab aggregation, disaggregating Ab brils, and protecting Abinduced cytotoxicity. The authors found that SWCNT-OH could inhibit Ab brillation and disaggregate mature brils in a dosedependent manner (Fig. 2B). Moreover, the related experience showed that the ratio of hydroxyl groups in SWCNT-OH played an important role in inhibiting Ab brillation. In detail, with the increase the ratio of hydroxyl groups, the inhibitory capacity of SWCNT-OH was greatly improved. Molecular dynamics (MD) simulations further revealed that the interactions between SWCNT-OH and the Ab 11-42 pentamer were found to be dominated by van der Waals interactions. In addition, the inter-and intra-peptide interactions of Ab brillation were signicantly weakened by hydrophobic interactions and p-p stacking of Ab and SWCNT-OH, and SWCNT-OH mainly interact with the six residues of Ab 11-42 (H13, H14, Q15, V36, G37, and G38). In our group, the structure of the Ab 42 monomer affected by tuning the curvature of carbon nanotubes was deeply studied using MD simulations. 49 The related research indicated that Ab 42 peptides had an extended structure and a larger number of contacts with the surface of C25. When the curvatures of the carbon nanotubes (CNTs) were high, the peptide wrapped around the CNTs and had less contact with the surfaces (Fig. 2C). Moreover, the CNTs with lower curvatures and the peptides had stronger interactions and induced the collapse of the initial secondary structures of the peptides. With decreasing curvatures, the peptides were arranged diagonally along the nanotube, and the percentages of a-helical structures were reduced. This research indicated that the structural stability, including the nucleation and self-assembly behavior of Ab 42 peptides on SWCNT surfaces, is dependent on the surface curvatures. The disaggregation mechanism of SWCNTs for mature Ab brils was also investigated. For instance, Lin et al. 50 explored the interplay between SWCNTs and Ab brils by atomic force microscopy, ThT uorescence, infrared spectroscopy, and MD simulations at the single SWCNT level. The results demonstrated that SWCNTs could partially destroy the mature Ab brils and form Ab-surrounded-SWCNT conjugates and cut down the b-sheet structures. Besides, MD simulation conrmed that the disaggregation ability was dependent on the binding sites of Ab brils (Fig. 2D).
Compared to SWCNTs, multiwalled carbon nanotubes (MWCNTs) possess obvious advantages, such as lower product cost, excellent chemical stability and drug adsorption potential. 51 Lohan et al. 52 designed a system of berberine (BRB)loaded MWCNTs with polysorbate and phospholipid coating. BRB was known to possess neuroprotective actions. Polysorbates and phospholipids have been reported to improve the imaging and targeting utility of CNTs. The results showed that the phospholipid-coated and the polysorbate-coated MWCNTs exhibited remarkable recovery in the memory performance.

Gold nanorods
Gold nanorods are rod-shaped gold nanoparticles with a size ranging from a few nanometers to hundreds of nanometers. 53 Gold is a precious metal material with very stable chemical properties. Gold nanoparticles inherit these properties of bulk materials, so they are relatively stable and have very rich physicochemical properties. 54 The surface plasmon resonance wavelength of gold nanorods can be changed with the aspect ratio, continuously adjustable from visible (550 nm) to nearinfrared (1550 nm), and an extremely high surface electric eld strength enhancement effect. 55,56 Gold nanorods have extremely high optical absorption, scattering cross-sections, and photothermal conversion efficiency that is continuously adjustable from 50% to 100%. 57,58 Therefore, Au nanorods (AuNRs) exhibit strong localized surface plasmon resonance (LSPR) in the near-infrared spectrum and have good performance in photothermal (PTT) therapy. 59,60 Gold nanorods as potential therapy nanomaterials have been utilized to modulate amyloid aggregation. AuNRs were functionalized with a metal-chelating group amide-nitrilotriacetic-Co II (ANTACo) to immobilize soluble RepA-WH1 selectively (Fig. 3A). In the presence of catalytic concentrations of anisotropic nanoparticles, H6-RepA-WH1 undergoes stable amyloid oligomerization. 61 Then, such oligomers promote the growth of amyloid bers of untagged RepA-WH1. Prionoid-functionalized AuNRs as nucleating agents for controlled protein amyloidosis in vitro. AuNR-mediated amyloid nucleation is based on a conformational change from the dimer protein precursor to the immobilized pre-amyloidogenic monomer at the nanoparticle surface, which effectively promotes the oligomerization and brillation of amyloid. Lin et al. 62 introduced a novel method where AuNRs combined with Ab brils can be efficiently destroyed under fs-laser irradiation without increasing the cytotoxicity. The fs-laser could trigger the nanoexplosion of AuNRs by LSPR and bring the Ab brils into non-b-sheet structure components. Sudhakar et al. 63 fabricated AuNRs and utilized them to inhibit the aggregation of Ab by a NIR laser. Meanwhile, the shape-dependent plasmonic properties of AuNRs are exploited to facilitate faster disaggregation of mature Ab brils. In addition, a related study found that 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) stabilized AuNRs can inhibit the formation of brils due to selective binding to the positively charged amyloidogenic sequence of Ab protein (Fig. 3B). This research exhibited a dual effect: inhibition of Ab brillation and NIR laser facilitated the dissolution of mature Ab brils. However, the role of heat generation by AuNRs, which promoted the disaggregation of brils, had not been explained from a molecular perspective. 63 Then Liu et al. 64 prepared CTABstabilized AuNRs with different sizes (CTAB as cetyltrimethylammonium bromide), and the effect of diameters and lengths of AuNRs on Ab brillation was in-depth studied. A related uorescence experiment indicated that in the presence of CTAB-stabilized AuNRs with different sizes, the formation of larger oligomers and brils was inhibited, and the inhibition efficiency decreased with the decrease of diameters of AuNRs (Fig. 3C). For the AuNRs with the same diameter, the inhibition efficiency decreased with the length of Au NRs. A CD experiment indicated that AuNRs with larger sizes inhibited the formation of a b-sheet structure to some extent. In summary, CTABstabilized AuNRs inhibited the kinetic process of Ab brillation, and the inhibition efficiency of larger AuNRs was better. Meanwhile, the sizes of AuNRs played a key role in modulating the kinetic aggregation process of Ab brillation. This work found that the rate constant had a positive relationship with the diameters or lengths of CTAB-stabilized AuNRs. Interestingly, Liu et al. 65 studied the NIR absorption properties of AuNRs loaded with a single chain variable fragment and thermophilic acylpeptide hydrolase as a smart theranostic complex GAS, which possesses both rapid detection of Ab aggregates and NIR photothermal treatment that effectively disaggregates Ab aggregates and reduces Ab-mediated toxicity (Fig. 3D). Morales-Zavala et al. 66 synthetized a polyethylene glycol stabled and dual-peptide modied gold nanorod complex. A related study determined that the nanoconjugate does not affect neuronal viability. The nanoconjugate could penetrate the cells and decrease the Ab peptide aggregation in vitro. Subsequently, Morales-Zavala et al. 67 also developed a neurotheranostic platform based on AuNRs, which works as a therapeutic peptide delivery system. As a diagnostic tool, the platform could be detected in vivo through microcomputed tomography (micro-CT). Ang2 and D1 peptide modied AuNRs induced the diminution of both the amyloid load and inammatory markers in the brain of the AD model. The differences in GNRs-D1/Ang2 between wild type (WT) and AD mice were observed in vivo. The two peptide modied AuNRs can improve the delivery and retention of this platform in the brain and reinforce the therapeutic benets associated with the b-sheet breaker ability of the D1 peptide.

Two-dimensional nanomaterials
Two-dimensional (2D) nanomaterials refer to nanomaterials that have only one dimension on the nanometer scale. 68 Because of their huge specic surface area and special surface structure, 2D nanomaterials can adsorb and interact with various molecules such as drugs, nucleic acids, peptides, and proteins. 69 Two-dimensional nanomaterials also have the ability to penetrate biological barriers. 70 Therefore, as a drug carrier, 2D nanomaterials can load numerous drugs and cross various biological barriers. 71,72 Meanwhile, 2D nanomaterials can also absorb and immobilize amyloid protein by interacting with interfaces. 73 Some 2D nanomaterials possess light-responsive properties and have great potential in photothermal and photodynamic therapy. 69,74 Two-dimensional nanomaterials have good peroxidase-like properties and can alleviate oxidative stress. 75 Based on the advanced properties, 2D nanomaterials have been attractive in AD diagnosis and treatment. 76 2D nanomaterials have been used in AD research, mainly including graphene nanosheets, carbon nitride nanosheets, black phosphorus nanosheets, and transition metal dichalcogenide nanosheets. Besides, some studies have shown that 2D MOFs, MXenes, hexagonal boron nitride and so on also have applications in AD diagnosis and treatment.

Graphene
Graphene or graphene oxide (GO), one of the two-dimensional nanomaterials, consists of mono-layer carbon atoms with conjugated p-p. 77 Due to the excellent electrical conductivity, ultra-high specic surface area, high mechanical strength, good biocompatibility, and photothermal conversion characteristics, graphene has been widely used in biomedical elds such as bioimaging, biosensing, and drug delivery. [78][79][80] Mahmoudi et al. 81 indicated that GO and protein-coated GO can delay the Ab brillization process via adsorption of amyloid monomers. Then Li et al. 82 further conrmed that the binding between the peptide monomer and the surface of the GO sheets can redirect the assembly pathway of Ab (Fig. 4A). Wang et al. 83 examined the size effect of GO on modulating amyloid peptide assembly and found that GO with a large size has a relatively stronger modulation effect for the aggregation of Ab [33][34][35][36][37][38][39][40][41][42] . The advantages of graphene nanocomposites are even more obvious. As shown in Fig. 4B, Ahmad et al. 84 successfully fabricated nanocomposites of iron oxide and graphene oxide (GOIO) using solvothermal methods. Due to the high surface area of GOIO, GOIO can effectively interact with Ab 42 , inhibit the formation of mature brils from Ab 42 monomers and maintain the secondary structure of Ab 42 into a random coil or a-helix-rich structure. Many researchers have worked to investigate the mechanism of action of graphene bias with Ab. The penetration and extraction of graphene were identied as two main mechanisms for scavenging brils (Fig. 4C). 85 This is because of the strong interaction between graphene and amyloid brils through p-p stacking and hydrophobic interaction due to the special sp 2 structure of graphene. Graphene nanosheets can extract single peptide molecules from mature amyloid brils into their surface, and the absorption interaction is further enhanced by p-p stacking because of the aromatic residues of Ab and the sp 2 structure of graphene. Chen et al. 86 investigated the oligomerization of Ab 33-42 by performing replica exchange MD simulations on Ab [33][34][35][36][37][38][39][40][41][42] peptide chains in the absence and presence of two different sizes of GO, and found that GO inhibited Ab 33-42 oligomerization by making Ab [33][34][35][36][37][38][39][40][41][42] peptides separate from each other. Jin et al. 87 revealed the mechanism of GO nanosheets in inhibiting Ab 42 aggregation through MD simulations, and found that GO mostly suppressed the b-sheet formation of Ab 42 by weakening inter-  84 (C) Graphene nanosheet penetration and Ab peptide extraction. Featuring two graphene sheets attacking a pre-formed Ab amyloid fibril from the same side, and the two graphene sheets attacking from both sides. 85 (D) GO-ThS effectively dissolve the amyloid deposits of Ab 40 upon NIR laser irradiation. 91 peptide interactions mostly via the salt bridge, hydrogen bonding and cation-p interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The p-p and hydrophobic interactions between GO and Ab 42 also play a key role in the inhibition of Ab aggregation. Meanwhile, Yin et al. 88 indicated that the adsorption capacity with Ab of graphene's surface varies signicantly depending on its curvature. The negative curved surface is more likely to adsorb Ab than the positive curved surface. These ndings showed that the shape of the nanoparticle is important in determining its interaction with the peptide. He et al. 89 investigated the thermodynamics and kinetics of bril elongation on GO surfaces with different oxidative degrees. This study revealed that the behaviors of GO in bril elongation depend on the balance between the promoting effect by templating the incoming of monomers and the retarding effect by capturing the monomer during docking and locking phases through hydrogen bonding. Subsequently, Li et al. 90 also further demonstrated that GO could clear amyloids by inducing microglia and neuron autophagy. Photothermal therapy can be used to dissolve mature Ab brils. As shown in Fig. 4D, Qu's group rstly reported the photothermal treatment for AD using graphene nanosheets. Thioavin S (ThS) which can specically bind to Ab bers was covalently linked to the surface of GO. The prepared GO-ThS nanocomposites have a uniform diameter of 100 to 200 nm, and the thickness of GO-ThS nanocomposites is about 1.5 nm. The related research showed that GO-ThS can cross the BBB, selectively interact with Ab 40 brils, and disaggregate Ab 40 brils under near-infrared (NIR) laser irradiation. Moreover, the decomposition of Ab 40 brils can be monitored by the uorescence changes of ThS in real time. 91 Xia and Maciel et al. 92,93 have reported a potential drug carrier for loading drugs using GO through non-covalent interactions. Wang et al. 94 prepared a novel nanocomposite GO@Dau from GO and dauricine (Dau), and the benzene ring on Dau can be adsorbed by GO by forming a non-covalent bond. GO@Dau will both have anti-inammatory and anti-oxidative stress capabilities and inhibit Ab misfolding. This study further found that GO@Dau can effectively enrich in the brain aer intranasal administration and GO@Dau can be internalized into the olfactory bulb by endocytosis or pinocytosis of olfactory neurons, and then released and distributed into the brain. More interestingly, researchers found that GO@Dau could increase superoxide dismutase levels, decrease reactive oxygen species and malondialdehyde levels in vitro, and attenuate cognitive memory decits and glial cell activation for AD mice.
Overall, graphene nanosheets and their nanocomposites have been reported for use in AD therapy. However, the specictargeted issue and drug delivery modalities of graphene still need to be elucidated. Especially, the BBB penetration of graphene is needed to be deeply researched. Through functionalization and size or shape adjustment for nanomaterials, utilizing paracellular pathway, transcellular lipophilic pathway, transport proteins, receptor-mediated transcytosis, and adsorptive-mediated transcytosis could achieve penetration of the BBB. 95,96 Although many investigators have studied and summarized the biodistribution characteristics, in vivo clearance, toxicity, and interactions with biological systems of GO, there is still much to be unveiled that would allow safe and effective therapy. 97,98

g-C 3 N 4
Graphitic carbon nitride (g-C 3 N 4 ) is the most stable allotrope of carbon nitride under ambient conditions. 99 g-C 3 N 4 has thermodynamic stability, good biocompatibility, low toxicity, and unique photocatalytic properties. [100][101][102] It has received extensive attention in biological applications in recent years. 103 In 2016, Li et al. rstly used g-C 3 N 4 as an Ab inhibitor for AD treatment. 104 As shown in Fig. 5A, g-C 3 N 4 nanosheets could effectively inhibit the formation of Ab aggregates, separate the preformed Ab-Cu 2+ aggregates, and reduce the intracellular reactive oxygen species (ROS) levels. Then, Li et al. 105 combined the advantages of g-C 3 N 4 nanosheets with some metal complexes to fabricate platinum(II)-coordinated g-C 3 N 4 nanosheets (g-C 3 N 4 @Pt), and g-C 3 N 4 @Pt was able to inhibit Ab brillation. As shown in Fig. 5B, g-C 3 N 4 @Pt could effectively inhibit the aggregation of Ab through non-covalent interaction and photooxidation. As shown in Fig. 5C, Wang et al. 106 prepared a nanocomposite which is named GO/g-C 3 N 4 by the sonochemical method. Under UV light irradiation, GO/g-C 3 N 4 could disaggregate mature Ab brils. GO could act as an Ab collector by adsorption interaction and g-C 3 N 4 could serve as a cleaner by photodegradation. Notably, the photodegradation efficiency of the composite could be kept high because the heterojunction between GO and g-C 3 N 4 helps to separate the photoexcited electron-hole pairs. In 2020, Wang et al. 107 reported a kind of novel gold nanoparticle modied g-C 3 N 4 (Au/g-C 3 N 4 ), which can effectively degrade preformed amyloid aggregates, and the photodegradation of amyloid aggregates mainly depends on the generation of oxygen radicals, especially hydroxyl radicals. As shown in Fig. 5D, Chung et al. 108 veried that g-C 3 N 4 can effectively inhibit the aggregation of Ab under light illumination. Under visible light irradiation, g-C 3 N 4 nanosheets could generate ROS through photo-induced electron transfer, and oxidize Ab protein, preventing Ab misfolding and brillation. The inhibition efficiency of g-C 3 N 4 for Ab aggregation will be increased with the concentration and absorbance intensity of g-C 3 N 4 under LED irradiation. Doping metal ions, such as iron, can help g-C 3 N 4 nanosheets accelerate the charge transfer activity, resulting in high ROS generation for inhibiting Ab aggregation. 109 g-C 3 N 4 has some inherent disadvantages, such as poor water solubility, relatively large particle size, and lack of absorption above 460 nm, but its reliable biocompatibility at certain doses proves its potential for biological applications. [110][111][112] For g-C 3 N 4 applications in living organisms, issues such as auto-uorescence, optical therapeutic efficiency, and in vivo clearance rates still need to be addressed. 103

Black phosphorus
Black phosphorus (BP) nanosheets, a novel two-dimensional layered semiconductor nanomaterial, have attracted extensive attention due to their good optical, thermal properties, photocatalytic properties, and biological compatibility. 113,114 BP can be degraded into non-toxic phosphate and phosphite anions under physiological conditions. 115 BP nanosheets can efficiently and selectively capture Cu 2+ to protect neuronal cells from Cu 2+ -induced neurotoxicity. 116 Moreover, due to the photothermal transition efficiency, BP nanosheets can cross the BBB by relying on NIR laser irradiation. 117 In 2019, Lim et al. 118 synthesized two kinds of typical BP nanomaterials with different sizes, titanium ligand-modied BP nanosheets (TiL 4 @BPNSs) and titanium ligand-modied BP quantum dots (TiL 4 @BPQDs). The results showed that TiL 4 @-BPNSs and TiL 4 @BPQDs inhibited Ab 40 aggregate by adsorbing Ab 40 monomers. Then, Yang et al. 119 designed a PEG-stabilized BP nano-system PEG-LK7@BP, which can effectively inhibit the formation of Ab 42 brils (Fig. 6A). In addition, as a peptide inhibitor, LK7 was coupled to the BP surface via electrostatic and p-p interactions. PEG was used to enhance the stability of BP. PEG-LK7@BP inhibited Ab 42 brillation in a dosedependent manner. Importantly, PEG-LK7@BP has no cytotoxicity to normal cells and can effectively alleviate the cytotoxicity induced by Ab. The inhibition ability of PEG-LK7@BP can be attributed to multiple effects: (1) PEG-LK7@BP can bind with Ab through electrostatic and hydrophobic interactions. (2) LK7 can enhance the targeted properties of PEG-LK7@BP for Ab amyloid. (3) PEG enhanced the stability and dispersibility of the nanomaterials. Cu 2+ can catalyze the production of ROS and cause neuronal apoptosis. 120 Therefore, it is needed to design novel nanomaterials for not only capturing excess metals but also crossing the BBB. As shown in Fig. 6B, Chen et al. 121 demonstrated that BP nanosheets can efficiently and selectively chelate Cu 2+ to inhibit neurotoxicity induced by Cu 2+ . Importantly, under the irradiation of a NIR laser, the BBB permeability of BP nanosheets is signicantly improved due to the photothermal effect.
Due to the properties of precise treatment and fewer side effects for various diseases, photodynamic therapy (PDT) has attracted extensive attention in the biomedical eld. 122,123 However, some photosensitizers suffer from low catalytic efficiency, a short absorption wavelength, poor biocompatibility, and non-degradability in living tissues. 124 In 2015, Wang et al. 125 rst demonstrated that exfoliated BP nanosheets are effective photosensitizers for generating 1 O 2 , and the quantum yield is  (Fig. 6C). These excellent properties make BP nanosheets photocatalysis nanomaterials in PDT therapy. As shown in Fig. 6D, Qu's group designed a near-infrared responsive nanomaterial based on BP nanosheets. 126 The authors also utilized BTA (one of the thioavin-T derivatives) to modify black phosphorus, aiming to recognize Ab and enhance BP stability. BP@BTA could generate 1 O 2 efficiently and the inhibition efficiency of Ab brillation was effectively heightened.
Compared with other 2D materials, BP exhibits a tunable energy bandgap from about 0.3 eV (bulk) to 2.0 eV (monolayer), allowing broad absorption across the entire ultraviolet and infrared regions. 127,128 Moreover, the degradable character of BP from element to nontoxic and biocompatible phosphorus oxides is endowed with good biocompatibility in vivo. 129

Transition metal dichalcogenides
Different from carbon or phosphorus-based two-dimensional (2D) nanomaterials, transition metal dichalcogenide nanosheets have become alternative candidates, such as MoS 2 and WS 2 . MoS 2 and WS 2 are sandwich structures composed of hexagonal metal atoms sandwiched between two layers of chalcogens. 130 Transition metal dichalcogenide nanosheets were shown to address biological and medical elds due to their novel nanoscale structures, rich physics, and high mobility. [131][132][133] The basal plane of transition metal disulde nanosheets can adsorb or conjugate various aromatic hydrocarbons (such as pyridine and purine) and other compounds. 134 In recent years, transition metal dichalcogenide nanosheets have been reported for drug delivery and tissue ablation. 135 In 2013, Chou et al. 136 prepared MoS 2 by a chemical exfoliation method and obtained a two-dimensional amphiphilic compound with good colloidal stability in aqueous media. Wang et al. 137 explored the effect of MoS 2 on the brillation process of Ab fragments and human islet amyloid polypeptide (hIAPP) fragments. A related study found that MoS 2 allows for concentration-dependent modulation of amyloid aggregation. Mudedla et al. 138 applied MD simulations to deeply study the interaction mechanism between amyloid brils and MoS 2based nanomaterials. MoS 2 -based nanomaterials cause the disruption of the secondary structure and change the b-sheet conformation to a ipped form. The results exhibited that the intermolecular force of peptides, including hydrophobic and hydrophilic interactions, was reduced due to the interaction between peptide and molybdenum disulde materials. More destabilization of the bril under nanotubes is observed compared to the nanosurfaces due to the difference in binding modes (Fig. 7A). Regrettably, no corresponding in vivo studies were performed. Liu et al. 139   AuNRs. MoS 2 /AuNR can disrupt mature brils under NIR irradiation and prevent Ab protein-induced neurotoxicity. It is worth mentioning that both MoS 2 nanosheets and AuNRs can be used as NIR photothermal agents, and the MoS 2 /AuNR nanocomposites enhance the ability to destroy Ab brils and enhance cell viability by generating localized heat under NIR irradiation (Fig. 7C). Because the specic cleavage sites of Ab are oen embedded in the b-sheet structure, articial enzyme inhibition efficiency is severely hindered in practical applications. Qu's group constructs a NIR controllable articial metalloprotease (MoS 2 -Co) using a MoS 2 nanosheet and a cobalt complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Codota). 141 MoS 2 -Co circumvented the b-sheet structural restrictions by simultaneous inhibition of the conformational switch from the random-coil to b-sheet structures and modulation of b-sheet structures of the preformed Ab brils (Fig. 7D).
Li et al. 142 found that WS 2 nanosheets could effectively inhibit Ab 40 aggregation. Under van der Waals forces and electrostatic interactions, Ab 40 monomers can be selectively adsorbed on the nanosheet surface. WS 2 has high NIR absorption properties, which can dissociate Ab 40 brils under NIR irradiation (Fig. 7E). Compared with traditional small molecular Ab inhibitors, WS 2 nanosheets can cross the BBB and exhibit excellent physicochemical characteristics.
The synthesis and modication methods of transition metal dichalcogenide nanosheets need to be further optimized. The preparation of nanosheets of specic thickness and size is essential. In addition, targeting issues and the biodegradation behavior of nanosheets need to be further explored.

Others
2D COFs, MXenes, hexagonal boron nitride and so on have also been reported for use in AD diagnosis and treatment. 120,143,144 Covalent organic frameworks (COFs) are a new generation of nanoparticles consisting of carbon, oxygen, nitrogen and hydrogen atoms with excellent biocompatibility. 145 2D COFs have a highly tunable structure and can be designed to cross the blood-brain barrier and inhibit Ab aggregation. Maleki et al. 143 combined experimental and molecular simulation tools to investigate the interaction of novel two-dimensional COF materials with Ab. The results indicate that aminefunctionalized COFs with large surface areas have the potential to inhibit Ab aggregation. Amine-functionalized groups were also found to enhance the ability of COFs to break the BBB. Two-dimensional transition metal carbides and/or nitriles (MXenes) possess a variety of enzyme-mimetic activities such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD), which can be used for ROS scavenging against oxidative stress-induced inammation and neurotoxicity. MXenes have good photothermal properties and improve the permeability of the BBB. Du et al. 120   photothermal conversion properties of Nb 2 C MXenzyme nanosheets give them the ability to cross the BBB non-invasively.
Boron nitride nanomaterials have good chemical stability, antioxidant properties and biocompatibility. Unlike carbon nanomaterials, boron nitride nanomaterials are less hydrophobic and can maintain the conformation of Ab rather than change it. Sorout et al. 146 found that the interpeptide contacts are largely reduced in the presence of (3,3) boron nitride nanotube (BNNT) and that the nanoparticle interacts with the trimer in such a way that the initial helical secondary structure of the Ab peptide is retained. The effect of different curvatures of boron nitride on Ab aggregation was then continued to be investigated. And it was found that the planar boron nitride nanosheet (BNNS) with zero curvature is found to prevent bsheet formation by converting the secondary structure of the peptide to dominant coil and turn conformations. 144 The total number of peptide-nanoparticle contacts increases with a decrease in the curvature and a corresponding increase in the nanoparticle surface area. In addition, boron nitride nanoparticles have been reported as nanocarriers/agents to ameliorate Ab-induced cytotoxicity. 147,148 Currently for boron nitride nanomaterials differences from carbon nanomaterials have been revealed. Further research is expected to lead to a new generation of AD therapeutic nano-agents. Table 1 lists the mechanism and effect of two-dimensional inhibitors on the modulation of amyloid aggregation.

Zero-dimensional nanomaterials
Zero-dimensional (0D) nanomaterials, including gold nanoparticles (GNPs), gold nanoclusters, organic and inorganic quantum dots, metal oxide nanoparticles, and carbon-based nanomaterials, have attracted extensive research interest in the eld of biomedicine in recent years. 149 The edge effect, quantum connement effect, ultra-small size and good biocompatibility of 0D nanomaterials endow them with many functions and special performance, such as photoluminescence (PL), tissue penetration, bioactivity, and drug loading capability. 149 Therefore, various 0D nanomaterials have been applied to diagnose and treat diseases, such as neurodegenerative disease, cancer and infection. 150 Moreover, some advanced 0D nanomaterials can overcome the BBB and inhibit AD-related amyloid aggregation, so they are utilized to treat Alzheimer's disease. [151][152][153] In this part, we summarized diverse treatment methods for amyloid and related neurodegenerative diseases by using different 0D nanomaterials.

Gold nanoparticles
Gold nanoparticles (AuNPs) have attracted great interest as a novel platform in catalysis, drug delivery, and disease diagnosis/treatment owing to their biocompatibility, intriguing optical properties, surface functionalization, and immunological properties. 154,155 Also, due to the diverse sizes, shapes, and surface properties, AuNPs have also been constructed to treat diverse central nervous system diseases. Moreover, AuNPs have been applied to modulate AD-related Ab brillation under intracellular/extracellular spaces. 156 Liao et al. 157 studied the surface charge of AuNPs by different surface functionalization modications for effecting Ab brillation. Interestingly, although bare and negatively charged AuNPs both could effectively inhibit Ab brillization and disaggregate Ab brils and spherical oligomers compared with positively charged AuNPs, the negatively charged AuNPs exhibited higher inhibition ability than bare AuNPs during Ab brillization-reduced neurotoxicity. Moreover, the neurotoxicity decreased only when incubated with bare and negatively charged AuNPs in a concentration-dependent manner (Fig. 8A). Apart from that, Wang et al. 158 also studied the different shapes and effects of AuNPs on the aggregation of Ab. The authors rstly prepared gold nanospheres (AuNSs) and gold nanocubes (AuNCs). The results of thioavin T uorescence assay showed that both AuNSs and AuNCs could inhibit Ab brillation, but the effect efficiency of AuNSs is stronger than that of AuNCs. As shown in Fig. 8B, the shape of AuNPs inuences the brillation kinetics of Ab and the morphologies of Ab brils. As a possible mechanism of shape-dependent AuNP-Ab interactions, the authors analyzed that the surface energy of AuNPs is key for driving interaction between peptides and NPs. The AuNPs with an enormous specic surface area will inevitably adsorb peptide molecules on their surface. Compared to AuNCs, the spherical surface produces a large density of low-coordinated atoms situated on the edges and corners of AuNSs. Therefore, AuNSs have a stronger interaction with Ab than AuNCs. Coincidentally, Tapia-Arellano et al. 159 also found that the shape of the AuNPs could affect the aggregation kinetics of Ab. They researched the effect of at gold nanoprisms (AuNPr) and curved gold nanospheres (AuNSs) on Ab aggregation kinetics and found that AuNPr accelerated the aggregation process and AuNSs slow down this process. The interaction mechanism between the surface of gold nanoparticles and Ab brils also needs to be studied with MD simulations. As shown in Fig. 8C, the AuNPs can interact with the amino-acid sequence of 31 IIGLMVGGVVI 41 . 160 Aer 10 ns, the AuNPs can move along the region of the b-sheet. Amino acids including Ile31, Gly33, Met35, Gly37, Val39, and Ile41 in Ab brils were involved in binding with AuNPs. John's group also investigated the inuence of AuNPs on peptide aggregation by studying the amyloid model peptides (Fig. 8D). 161 They designed citrate-modied AuNPs and used MD simulations to conrm the structure-forming properties of the citrate-gold surface. They found that peptide monomers presented favored N-terminal adsorption to the surface of citrate-modied AuNPs by electrostatic attraction. Based on MD simulations, it was concluded that the initial contact of charged groups with the gold surface resulted in a local elevation and alignment of peptide monomers on the surface.
Besides studying citrate-modied AuNPs, biomolecular functionalized AuNPs have also been investigated. Scutellaria barbata leaf extract mediated AuNPs and mimosine functionalized AuNPs have also been identied to suppress AD-related bamyloid aggregation and neuronal toxicity. 162,163 However, the interactions between AuNPs and Ab are typically nonspecic, and thus it is a great challenge to specically target Ab by using AuNPs. In addition, most studies have only focused on the simple surface-interface interactions between Ab and AuNPs, the potential function needs to be deeply tapped. Therefore, Xiong et al. 164 designed a kind of dual peptide coupled AuNPs. As one of the functional peptides, the VVIA (Ab 39-42 ) fragment can specically target Ab and efficiently reduce Ab-induced toxicity by generating nontoxic heterooligomers. Meanwhile, LPFFD can efficiently interact with the KLVFFAE of the central hydrophobic cluster of the Ab sequence. As a result, the inhibition ability of the corresponding peptide@AuNPs against Ab aggregation and cytotoxicity is greatly improved. Thereaer, the dual peptide modied AuNPs (VVIACLPFFD (VCD10)@AuNP) are the most effective in inhibiting Ab oligomerization and the cytotoxicity caused by the aggregation species.

Gold nanoclusters
Unlike AuNPs, gold nanoclusters (AuNCs) with a core size below 2 nm consist of a few to several hundred Au atoms. 165 Thanks to their unusual properties, including strong photoluminescence, signicant Stokes shi, good biocompatible, and biodegradation characteristics, AuNCs have been applied to disease-related diagnosis and treatment. 165 Especially as an innovative nanomedicine, AuNCs also have signicant promise in amyloidrelated disease applications.
As shown in Fig. 9A, Gao et al. 166 reported nanoclusters (AuNCs) for the inhibition of amyloid aggregation. The authors prepared L-glutathione stabilized AuNCs and found that AuNCs with smaller sizes could completely inhibit amyloid aggregation and efficiently prevented Ab from aggregation to larger oligomers, thus avoiding nucleation to form brils. As shown in Fig. 9B, Shi et al. 167 designed a novel dual-responsive "cage metal chelator" release system based on AuNCs for non-invasive remote control to promote clioquinol (CQ) release and solubilize Ab deposition. As a redox-and temperature-sensitive molecule, arylboronic esters were utilized to modify AuNCs for functionalized AuNCs. Therefore, the arylboronic ester-modied AuNCs could serve as a delivery system for H 2 O 2responsive controlled release. In addition, AuNCs possess a high near-infrared absorption and can further enhance the release of chelators under NIR light. As a result, this system can effectively inhibit Ab aggregation and protect neurons from Abreduced toxicity. Moreover, the photothermal effect of AuNCs can also serve as an effective means to dissolve Ab amyloid deposits. Zhang et al. 168 reported one type of Cys-Arg (CR) dipeptide modied Au nanocluster (Au 23 (CR) 14 ) that was able to effectively dissolve pre-formed Ab brils into monomers and recover the natural unfolded state of Ab peptides from misfolded b-sheets (Fig. 9C). In addition, Au 23 (CR) 14 was able to cross the BBB and cleared endogenous Ab plaques in the brain of transgenic AD model mice. However, the interactions between traditional AuNCs and Ab are also typically nonspe-cic, and thus it is also a great challenge to specically target Ab by using AuNPs. Recently, Hao et al. 169 used a peptide fragment (CLVFFA) to modify AuNCs (AuNCs-CLVFFA) and CLVFFA could target binding the central hydrophobic region LVFFA of Ab (Fig. 9D). Because the LVFFA is the central hydrophobic fragment of Ab and can inhibit the aggregation of Ab, AuNCs-CLVFFA was able to effectively inhibit Ab aggregation and prolongation and disaggregate mature brils. Moreover, AuNCs-CLVFFA inhibited the transformation of Ab from a random coil to a b-sheet structure.
We can also imagine the future development of functionalized AuNCs for amyloid aggregation-related diseases. With the deepening of research, we expect versatile AuNCs to become an essential platform for AD research.

Metal oxide nanoparticles
Metal oxide nanoparticles such as CeO 2 NPs, ZnO NPs, CuO NPs, and Fe 3 O 4 NPs have a variety of functional properties such as UV-barrier, antimicrobial, antioxidative, catalytic, and magnetic properties. 170,171 Therefore, they have been extensively used in the eld of drug delivery, disease diagnosis, disease treatment, and enzyme immobilization. 172 Among them, CeO 2 NPs, ZnO NPs, and Fe 3 O 4 NPs have also been researched in amyloid aggregation-related neurodegenerative disorders.
Due to their nontoxic nature, excellent biocompatibility and signicant antioxidant activity at physiological pH values, cerium oxide nanoparticles (CeO 2 NPs) have been given special attention. 173 In addition, CeO 2 NPs have both superoxide dismutase (SOD) mimetic activity and catalase mimetic activity by the Ce 3+ /Ce 4+ valence transition, which also provides CeO 2 NPs with an extra antioxidant function. 174 Recently, CeO 2 NPs have been used to protect neuron cells from Ab-induced damage and treat neurocentral disease. In addition, CeO 2 NPs can cross the BBB. Therefore, CeO 2 NPs can be a promising candidate for treating AD. Recently, Li et al. 173 designed a novel double delivery platform, which combined the advantages of controlled-release systems with those of glucose-coated CeO 2 NPs (G-CeO 2 NPs). G-CeO 2 NPs could specially release the CeO 2 NPs and Cu 2+ chelators by H 2 O 2 stimulation. Therefore, the G-CeO 2 NPs possess anti-aggregation properties and anti-oxidation properties. In addition, Li et al. adopted mesoporous silica nanoparticles as the carrier vehicles for loading G-CeO 2 -NPs and 5-chloro-7-iodo-8-hydroxyquinoline. The research result showed that G-CeO 2 NPs could effectively inhibit Ab aggregation, decrease cellular ROS and protect neurons from Ab-induced toxicity. Guan et al. 174 designed a bifunctional nanozyme (namely CeONP@POMs) by coating CeONP with POMs. The authors found that CeONP@POMs effectively inhibited Ab aggregation, degraded Ab aggregates, and reduced ROS levels. Moreover, CeONP@POMs is able to cross the BBB, regulate microglia, and protect neuronal cells from Ab-related cytotoxicity. Coincidentally, a multifunctional AD therapeutic system, namely CeNP@MnMoS 4 , was designed and used to maintain metal ion homeostasis, reduce oxidative stress levels, and promote cell differentiation. 175 Furthermore, due to the SOD activity, CeNP@MnMoS 4 can protect cells from oxidative stress. Based on the catalase and superoxide dismutase activity of CeO 2 and the hot electrons produced by gold nanorods, Ge et al. 176 designed dumbbell-shaped nanocomposites (Au-CeO 2 ) by coating both ends of gold nanorods with CeO 2 NPs, and endowed Au-CeO 2 with photocatalysis and photothermal effects in the NIR (Fig. 10A). To further improve the therapeutic efficiency of Au-CeO 2 , the authors used Ab-targeted peptides (KLVFF) to modify Au-CeO 2 and obtained an Abtargeted nanocomposite (K-CAC). The related results exhibited that K-CAC could improve the cognitive function of AD mice.
As a type of magnetic nanoparticles (MNPs), iron oxide nanoparticles (IONs) are considered promising materials due to their high biocompatibility, unique magnetic properties, and ability to function as multimodal contrast agents. 177,178 In addition, IONs have potential high affinity for circulating Ab forms to induce a "sink effect" and potentially ameliorate AD. 179 Mahmoudi et al. 178 found that lower concentrations of superparamagnetic iron oxide nanoparticles (SPIONs) inhibited brillation, while higher concentrations increased the rate of Ab brillation. And it was evident that the positively charged SPIONs could promote brillation compared with negatively charged or uncharged SPIONs. Currently, the surface functionalization of nanoparticles by using chemical methods is becoming more and more popular. Qu's group designed a multi-functional nanosystem (MNP@NFP-pep) by modifying a naphthalimide-based uorescent probe and KLVFF peptide on the surface of magnetic nanoparticles, which can both specically detect Ab oligomers and achieve the wireless deep magnetothermally mediated disaggregation of Ab aggregates with an alternating magnetic eld. 180 MNP@NFP-pep can interact with the exposed hydrophobic residues of Ab oligomers based on p-p stacking and hydrophobic interaction (Fig. 10B). MNP@NFP-pep was able to specically target Ab aggregates and break down Ab aggregates. Recently, our group presented drugbased magnetic imprinted nanoparticles (MINs@EGCG) combined with epigallocatechin-3-gallate (EGCG) and magnetic nanoparticles. 19 MINs@EGCG exhibited triple functions for amyloid inhibition, drug delivery and ber separation under an external magnet. MINs@EGCG inhibited the formation of amyloid brils with a high efficiency for 80%. Moreover, with the help of an external magnetic eld, the cleaning efficiency is up to 80%. In addition, Halevas et al. 181 prepared a nanocarrier (MMSNPs) by the sol-gel method using a magnetic core of  Thanks to the advantages of the Fe 3 O 4 cores, B-FeCN entered the brain and targeted the Ab region with the help of a magnetic eld. Benzothiazole aniline (BTA) makes B-FeCN a detection agent for specically targeting Ab plaques and imaging the Ab species by uorescence. However, B-FeCN has a certain biological toxicity, and the research on the metabolic mechanism in vivo is not perfect, which hinders further applications.

Organic and inorganic quantum dots
Therapeutic agents should be completely cleared from the body in a reasonable time, and usually, effective renal and hepatic clearance requires drugs less than 10 nm, and the development of nanoparticles with excellent biocompatibility is of great importance. 183 Sun et al. 184 prepared BPQDs with excellent NIR photothermal properties and biocompatibility using the liquid phase exfoliation method. The size distribution of the prepared BPQDs was only 2.6 nm. BPQDs were conjugated with PEG and exhibited high stability in the physiological medium and low toxicity for different cell types. More importantly, BPQDs induced the death of C6 and MCF7 cancer cells under NIR illumination, indicating that the BPQDs have great potential as photothermal agents with implications for the treatment of amyloid-related diseases. Wang et al. 185 found that BPQDs at 100 ng mL −1 inhibited insulin aggregation and disaggregated mature bers, and the inhibitory effect persisted through all stages of insulin aggregation (Fig. 11A). Molecular dynamics simulations showed that BPQDs could stabilize the a-helix structure of insulin and reduce the b-sheet content. Bu et al. 186 reported using BPQDs as a photoactive material and heme as an electron acceptor sensor to monitor the Ab protein content, and these properties make BPQDs a promising candidate for the treatment of amyloidosis and neurodegenerative disease.
Molybdenum disulde quantum dots (MoS 2 QDs) have been widely used for live bioimaging and nanomedicine because of their low toxicity, excellent cell permeability and biocompatibility, and strong luminescence properties. 187,188 Sun et al. 189 used a one-pot hydrothermal method to synthesize cysteamine functionalized MoS 2 QDs, which effectively inhibited the brillation and destabilized preformed brils of bovine serum albumin in a concentration-dependent manner. Li et al. 190 observed cell membrane perturbation and actin reorganization, which were induced by Ab oligomers. Further research revealed that the ultra-small MoS 2 QDs restored membrane uidity and inhibited Ab amyloid aggregation (Fig. 11B). Based on the calculation of discrete molecular dynamics simulations, it was found that MoS 2 QDs were bound to the N-terminal of Ab peptides through hydrophilic interactions. In addition, surfacecoated Ab oligomers by MoS 2 QDs could not further associate with cell membranes. Tian et al. 191 pointed out the promising application of MoS 2 QDs in photodynamic therapy. MoS 2 QDs promote the creation and separation of electron-hole pairs more effectively than MoS 2 nanosheets. Therefore, MoS 2 QDs are able to generate a variety of ROS under illumination. Results related to MoS 2 QDs broaden the application of molybdenum disulde-based nanomaterials.
As drugs or nanocarriers, selenium nanoparticles have made important progress in cancer, AD and other diseases because of their excellent physicochemical characteristics. 192 It has been reported that selenium nanoparticles have a high affinity for Ab, which can inhibit Ab aggregation and treat AD as a potential nanomedicine. 193 As shown in Fig. 11C, Guo et al. 194 synthesized selenium quantum dots (Se QDs), which could quickly penetrate the BBB because of their ultrasmall size and excellent biocompatibility. Se QDs had a strong free-radical scavenging activity and could protect cells from oxidative stress damage. Se QDs could not only inhibit Ab aggregation and reduce Abmediated cytotoxicity, but also effectively reduce tau protein phosphorylation, further improve oxidative stress, and maintain nerve cell stability. In conclusion, Se QDs had great advantages compared with traditional single-target drugs in the treatment of AD.

Carbon-based zero-dimensional nanomaterials
Carbon nanomaterials are widely used to inhibit Ab aggregation due to the various surface and interface interactions between the Ab peptide and carbon nanomaterials. 34 Carbon dots (CDs), as a new type of carbon-based zero-dimensional nanomaterial, have attracted extensive research in recent years because of their low cost, easy synthesis, good biocompatibility, photoluminescence, easy surface modication, and high stability. 195 It's important to note that CDs include graphene quantum dots (GQDs), carbide polymer dots (CPDs), and carbon quantum dots (CQDs). 196 GQDs are single-or few-layered graphene sheets of 10 nm or less in size. 197 Most CDs possess size-dependent auto-uorescence originating from quantum connement and edge effects, compared with carbon nanotubes, fullerenes, and graphene nanomaterials. 198 According to previous studies, GQDs have a good ability to cross the BBB, effectively modulate the Ab aggregation process and reduce Ab-induced neurotoxicity. 95 Therefore, GQDs are oen combined with Ab aggregation inhibitors or neuroprotective peptides to enhance efficacy. In 2015, Liu et al. 199 prepared GQDs by a hydrothermal method, demonstrating that GQDs effectively inhibited Ab 42 peptide aggregation (Fig. 12A). Moreover, Xiao et al. 200 prepared a novel nanomaterial GQDG by conjugating GQDs with glycineproline-glutamate (Gly-Pro-Glu). In vitro assays proved that both GQDs and GQDG could inhibit the aggregation of Ab 42 . In vivo assays indicated that GQDG enhanced AD model mice's learning and memory capacity, increased dendritic spine amounts, and decreased several pro-inammatory cytokine content. Subsequently, several studies reported the application of nitrogen-doped graphene quantum dots (N-GQDs) and uorine-functionalized graphene quantum dots (FGQDs) in amyloid aggregation. 201,202 Liu et al. 203 covalently combined GQDs with tramiprosate to design a novel Ab aggregation inhibitor, namely GQD-T. GQD-T showed the capability of inhibiting Ab aggregation and rescuing Ab-induced cytotoxicity due to the synergistic effect of the GQDs and tramiprosate (Fig. 12B). Moreover, GQDs can effectively disperse mature amyloid-rich Staphylococcus aureus biolms and interfere with the self-assembly of amyloid bers. 204 Liu et al. 205 studied the regulatory effects and mechanism of GQDs on Ab 42 aggregation and found that electrostatic interaction was the major driving force in the co-assembly process of Ab 42 and GQDs. Tak et al. 206 used Clitoria ternatea as a precursor with the help of a one-pot microwave-assisted method to prepare novel graphene quantum dots ctGQDs. The transport efficiency of ctGQDs across the BBB was increased signicantly and showed high inhibition efficiency of the acetyl cholinesterase enzyme. Meanwhile, Perini et al. 207 reviewed the potential of GQDs in biomedicine and neuroscience and discussed the ability of GQDs to cross the BBB and reach the brain. Ghareghozloo et al. 208 studied the inhibiting effect of graphene oxide quantum dots (GOQDs) on bovine insulin and hen egg white lysozyme (HEWL) aggregation. GOQDs were prepared through pyrolysis of citric acid, and the reduction step was carried out using ascorbic acid. The results showed that GOQDs could inhibit the related protein brillation, and the presence of reduced GOQDs was found to promote protein assembly via shortening the nucleation phase. The content of oxygen-containing functional groups from the GOQD surface may be the key factor in affecting brillation (Fig. 12C).
The detection of the concentration of amyloid monomer is of great importance in diagnosing AD. Huang et al. 209 proposed a method to detect Ab monomer concentration using the uorescent properties of GQDs (Fig. 12D). The positively charged groups, the aromatic structure and moieties with hydrogen bonding ability on Ab 42 monomers provided suitable conditions for the interaction between Ab 42 monomers and GQDs. This strong combination promoted the excited-state electron transfer from GQDs to Ab 42 , resulting in quenching of the PL intensity of GQDs. The Ab bers consume abundant interaction sites and contact surface areas through a self-assembly process, and the interaction between Ab bers and GQDs is much weaker to quench GQD uorescence. Yousaf et al. 210 reported the detection of monomers and oligomers using specic uorescence and a magnetic resonance imaging (MRI) multimodal probe based on bovine-serum-albumin-capped uorine functionalized GQDs (BSA@FGQDs). BSA@FGQDs could monitor amyloid brillation and was more sensitive than conventional ThT stain. Monitoring amyloid aggregation dynamics and monomers/oligomers using BSA@FGQD probes is based on hydrophobic, electrostatic, hydrogen bonding, and p-p stacking interactions. Tang et al. 211 examined the inuences of GQDs on the obstruction of the membrane axis of Ab in its three forms of monomers (Ab-m), oligomers (Ab-o), and amyloid brils (Abf), and demonstrated the mitigation potential of GQDs in reverting SH-SY5Y cells to their native uidic state. It was found that Ab-m is bound to the GQDs via strong electrostatic and hydrophobic interactions. The nanostructures reshaped the potential of mean force (PMF) of Ab-o to inhibit the b-sheet propensity of the peptide residues, and GQDs adhered to the sides and ends of an Ab-f, thereby hindering their elongation.
CQDs are a new class of 0D carbonaceous nanomaterials with a diameter less than 10 nm. 212 CQDs can be produced using diverse bioorganic compounds through solvent-free pyrolysis, hydrothermal treatment, or microwave treatment. These treatment methods and bioorganic compounds allow for the synthetic exibility of CQDs without intricate set-ups. 213 CQDs have outstanding features such as low cost, easy synthesis, excellent biocompatibility, and photoluminescence. 212 The absorption and emission spectra of CQDs can be tuned by adjusting the precursor type, preparation method, degree of carbonization, surface state, and element doping. 214 In addition, CQDs have abundant functional groups, such as hydroxyl, amino, and carboxyl groups, which are easy to modify. 215 Moreover, CQDs can interact with Ab peptides and aggregates through electrostatic, hydrogen bonding, p-p stacking, and hydrophobic interactions. 15,216 Many studies have reported the inhibition of human insulin brosis by using carbon dots. 217,218 Malishev et al. 219 prepared enantiomeric carbon dots (L-Lys-C-dots and D-Lys-C-dots) using L-lysine or D-lysine. The results demonstrated that L-Lys-C-dots exhibited higher affinity to Ab 42 (either monomeric and/or pre-brillar species) compared with D-Lys-C-dots, modulated the bril assembly process of Ab 42 (Fig. 13A). The authors speculated that the different properties of L-Lys-C-dots and D-Lys-C-dots were caused by residual lysine moieties which exposed to the C-dots' surface and residual lysine possibly interfered with the electrostatic interactions of the peptide. Zhou et al. 15 used o-phenylenediamine and citric acid as precursors to synthesize amphiphilic yellow-emissive CDs (Y-CDs) by an ultrasonication-mediated methodology. The amphiphilicity of Y-CDs didn't change with different coatings. In addition, it was proved that Y-CDs could cross the BBB of zebrash via passive diffusion. The related research suggested that Y-CDs could inhibit the overexpression of APP and Ab peptides. Koppel et al. 220 used brown coal to prepare novel CQDs. CQDs were able to inhibit IAPP and Ab aggregation induced by lipopolysaccharide (LPS) through hydrogen bonding and hydrophobic interactions. This study contributed to understanding the pathological link between bacterial metabolites and amyloid diseases. Due to the excellent antioxidant capacity of selenium nanoparticles, Zhou et al. 221 designed selenium-doped carbon quantum dots (Se-CQDs) via a simple hydrothermal treatment of selenocystine, which were successfully applied to inhibit Ab aggregation and scavenge the redundant ROS in the brain (Fig. 13B). Se-CQDs maintained the intrinsic properties of both selenium and CQDs. Se-CQDs have paired a-carboxyl and amino groups at their edges, which trigger multivalent interactions with Ab. Li et al. 222 fabricated Se-CQDs using selenocysteine through hydrothermal treatment under mild conditions. ROS could be effectively scavenged by the Se-CQDs. Once Se-CQDs are internalized into cells, high levels of ROS in cells are reduced. These properties enable Se-CQDs to protect biological systems from oxidative stress. Guerrero et al. 223 used Na-citrate as a precursor to prepare CQDs. Pulse-chase lysozyme bril-forming assay and ThT uorescence showed that CQDs prevented the monomers and oligomers into mature brils, while could provoke the disaggregation of mature HEWL brils. Li et al. 224 fabricated ultrasmall CQDs with a uniform size by pulsed laser ablation. Results demonstrated that CQDs could efficiently inhibit Ab 42 aggregation. Moreover, the quenching of tyrosine and ANS uorescence of the Ab 42 solutions with CQDs indicated that there existed an interaction between the CQDs and Ab 42 peptides. Our group prepared glycosylated carbon dots (g-CDs) using glucose as a precursor. gCDs-E has been prepared by selfassembly of gCDs and epigallocatechin-3-gallate (EGCG). gCDs-E could not only suppress the brillation of Ab and disaggregate Ab brils, but also effectively inhibit the activity of Candida albicans. 13 In addition, the capability of gCDs-E for BBB penetration was also observed using a normal mice model.
As a highly active substance, ROS can be used as a disease treatment agent. 225 At present, there are many research studies about photodynamic therapy for tumor diseases. 226 In addition, photodynamic therapy also has good application potential in amyloid-related diseases. 227 The band-to-band transition of CDs' electron carriers generates ROS through an electron-(type I) or energy-transfer (type II) process, mediating photomodulation to denature target biotoxins. 228,229 Like a type II photosensitizer, CQDs can react with oxygen aer absorbing energy, promote the production of singlet oxygen, and oxidize the amino acid residues of Ab peptides, thereby destroying the interaction between peptides. 230 For example, Chung et al. 231 synthesized CDs using ammonium citrate through one-pot hydrothermal treatment and obtained branched polyethylenimine modied CDs (bPEI@CDs) by passivating the surface of the prepared CDs using branched polyethylenimine. bPEI@CDs exhibited hydrophilic and cationic surface properties, which could effectively interact with negatively charged residues of Ab peptides. Under light illumination, bPEI@CDs displayed a strong effect on Ab aggregation and on the disaggregation of brils by generating ROS. Building on previous work, Chung et al. 232 prepared multifunctional carbon-dots (OPCDs) using o-phenylenediamine. The Ncontaining polyaromatic surface of OPCDs is the reason why the self-assembly of Cu(II)-Ab is hindered, thereby weakening Cu(II) catalyzed oxidative stress and Ab aggregation propensity. Illumination treatment further enhanced the inhibitory effect of OPCDs, which produced ROS to oxidize the key residues (His and Met) of Ab (Fig. 13C). Recently, Chung et al. 229 designed Abtargeted, red light-responsive apta@CD based on previous work, which inhibited Ab aggregation in space and time and reduced the overall Ab burden in the brain. Under red light, apta@CDs effectively inhibited the formation of Ab aggregates by oxidizing Ab residues, exhibiting a light-modulating effect on Ab aggregation (Fig. 13D). The application of apta@CDs to 5xFAD mice further demonstrated the anti-amyloid aggregation ability of apta@CDs in vivo.
CPDs have also been reported for AD diagnosis and treatment. Gao et al. 233 prepared multifunctional nitrogen-doped CPDs by using o-phenylenediamine for targeting Ab aggregations. CPDs inhibited Ab brillation and disaggregated Ab brils through electrostatic interactions, hydrogen bonds, and hydrophobic interactions. CPDs could emit enhanced red uorescence upon interaction with Ab brils, clear amyloid plaques in vivo and prolong the lifespan of CL2006 strain by alleviating Ab-induced toxicity. C 60 has been demonstrated to interact and prevent Ab brillation. However, there are signicant problems such as low solubility and toxicity that need to be solved.
Fullerenes and their derivatives have been reported for use in amyloid diseases. Melchor et al. 234 synthesized diethyl fullerenemalonates and the corresponding sodium salts using the Bingel reaction, adducts of C 60 bearing 1 to 3 diethyl malonyl and disodium malonyl substituents (C 60+n (COOR) 2n , where n = 1-3 and R = -CH 2 CH 3 , -Na). The inhibition efficiency of bisadduct salts (C 62 (COONa) 4 ) and trisadduct (C 63 (COONa) 6 ) is 98% and 83% respectively. The 6.7 mM C 62 (COONa) 4 mixture has been conrmed the capacities for anti-amyloid deposition. The anti-aggregation effect of C 62 (COONa) 4 is mainly attributed to the hydrophobic surface and the number of substituents bound on the surface of fullerene. C 60 acts as both a ROS producer under UV-visible light and a ROS scavenger in the dark. 235 Du et al. 236 designed UCNP@C 60 -pep nanoparticles, which generated ROS under NIR light and oxidized Ab. Moreover, UCNP@C 60 -pep could also alleviate the excessive ROS in the organization. Both the ROS generation and ROS quenching abilities of UCNP@C 60 -pep were benecial to reduce Abinduced neurotoxicity. Bobylev et al. 237 studied the ability of water-soluble fullerene derivatives with different types of solubilizing addends for anti-amyloid aggregation. The three derivatives were found to exhibit strong anti-amyloid effects in vitro and low cytotoxicity in vivo. The fullerene derivatives have a strong anti-amyloid effect and low toxicity. Their ability for crossing the BBB and the inhibition ability of amyloid brillation make fullerenes potential drug candidates. Table 2 lists the mechanism and effect of carbon-based zero-dimensional nanomaterials on the modulation of amyloid aggregation.

Others
In addition, other nanoparticles have also been reported for diagnosis and treatment of AD, including metal-organic

Metal-organic frameworks
Metal-organic frameworks (MOFs) are crystalline entities composed of metal ions or clusters and polydentate organic ligands. 242 As an emerging family of hybrid nanomaterials, MOFs have attracted much attention due to their porous structures, good biocompatibility, and tunable sizes, and are widely used in catalytic, sensing and biological applications. [243][244][245][246] Wang et al. 238 prepared NIR responsive nanoparticles PCN-224 for inhibiting Ab aggregation. PCN-224 was hydrothermally synthesized by coordinating tetrakis(4-carboxyphenyl) porphyrin (TCPP) ligands with zirconium (Fig. 14A). Under NIR irradiation, PCN-224 signicantly reduced Ab induced cytotoxicity. The functional porphyrin linkers are separated by Zr clusters in the MOF framework, which could avoid the selfquenching of excited states, maintain the photo-oxidative properties of the porphyrin linkers, and improve the 1 O 2 generation capacity. Yu et al. 247 selected four kinds of POMFs (Zr-MOF, Al-MOF, Ni-MOF, and Hf-MOF) for further investigation, which are stable under physiological conditions and exhibit excellent biocompatibility (Fig. 14B). It was found that Hf-MOF was the most efficient Ab photooxidant based on the experimental results and DFT calculations. LPFFD modied Hf-MOFs not only effectively targeted Ab peptides and reduced Abinduced cytotoxicity, but also improved photooxidation in complicated environments. Yan et al. 248 synthesized a core-shell nanocomposite CeONP-Res-PCM@ZIF-8/PDA/Apt through an in situ encapsulation strategy. Resveratrol (Res), ceria nanoparticles (CeONPs) and PCM (tetradecanol) were embedded in a ZIF-8/PDA matrix by a water-based mild method (Fig. 14C). These nanocomposites can be activated to release the encapsulated Res upon NIR illumination through PCM regulation. Moreover, CeONP-Res-PCM@ZIF-8/PDA/Apt nanocomposites exhibited multifunctional effects on inhibiting Ab aggregation, disaggregating Ab brils, and decreasing Ab-induced oxidative stress and neural apoptosis. The therapeutic effect of nanocomposites could be enhanced under NIR irradiation because of the excellent photothermal properties of PDA. In 2021, Zeng et al. 249 built an electron-decient MOF from the ligand of naphthalene diimide (NDI) and metal nodes of biocompatible Ca 2+ . Then pyrene as an electron donor molecule was encapsulated to form a host-guest MOF self-assembled co-crystal Py@Ca-NDI. A concomitant superior charge transfer interaction between pyrene and NDI could be attained and the photothermal conversion efficiency of Py@Ca-NDI in aqueous solution could reach up to 41.8%. The treatment of neurodegenerative disease by using MOF-based materials is a challenging study, and more elaborative studies on biostability, biocompatibility and BBB penetration are still needed. 250

Polyoxometalates
Polyoxometalates (POMs) are a special group of inorganic redoxactive materials consisting of multiple metal oxide ions linked together by oxygen atoms to form nanoclusters within an ordered three-dimensional framework. 251 Due to the tunable structures, excellent physicochemical properties and good biocompatibility of POMs, many researchers have explored their application in biomedicine. POMs can act as Ab aggregation inhibitors and can be seen as candidates for the treatment of AD because of their similarity to water-soluble fullerene derivatives. 252 In 2011, Qu's group reported the inhibitory effect of POMs on Ab aggregation and found that POMs with a Wells-Dawson structure had a better effect. 239 Then Li et al. 253 reported that POMs could not only inhibit Ab aggregation but also photodegrade Ab aggregates, such as Ab oligomers. Meanwhile, Li et al. 254 designed bifunctional nanoparticles POM@P through the self-assembly of Ab 15-20 peptides and POM (Fig. 15A). The aggregation process of Ab was researched by monitoring the uorescence of Congo red's aer adding POM@P. Moreover, the prepared POM@P could effectively target amyloid aggregation in mouse cerebrospinal uid. The interaction between POMs and Ab species relies on an electrostatic effect. Gao et al. 255 designed a variety of transition-metal-substituted POMds that had better inhibition efficiency of Ab aggregation than POMs. Results demonstrated that POMds with histidinebinding sites could not only specically target the polypeptide sequence (HHQK) of Ab, but also show stronger inhibitory effects through enhancing binding affinity between Ab and POMds (Fig. 15B). POMds-Dawson-Ni and POMds-Dawson-Co exhibited better effects for decreasing Ab-haem peroxidaselike activity. In addition, POMds could across the BBB and were metabolized completely aer 48 hours. Then Gao continuously designed articial enzymes AuNPs@POMD-8pep that exhibited protease activities, SOD-like functionality, and metalion chelation capabilities (Fig. 15C). 256 AuNPs facilitated electron transfer and served as a scaffold to create a coupled POMDpeptide compound.
Ab brils and ROS are closely related to AD pathogenesis. The reduced POMs (rPOMs) had a strong NIR absorption and ability for anti-oxidant activity. [257][258][259] Ma et al. designed a NIRresponsive rPOM-based agent rPOMs@MSNs@copolymer that consists of mesoporous silica nanoparticles (MSNs), rPOMs, and thermal responsive copolymer poly(N-isopropylacrylamideco-acrylamide). 252 The copolymer could melt under 808 nm irradiation and led to the release of rPOMs. Therefore, preformed Ab brils could be disaggregated by local heat. Zhao et al. reported an organic platinum-substituted POM with a Kegging structure (Me 4 N) 3 [PW 11 O 40 (SiC 3 H 6 NH 2 ) 2 PtCl 2 ] (abbreviated as Pt II -PW 11 ) (Fig. 15D). 29 The negatively charged Pt II -PW 11 anions could bind to the cationic cluster (HHQK) of Ab through electrostatic interaction, and Pt II -PW 11 interacted with other residues through van der Waals force, hydrogen bonding and desolvation energy. Pt II -PW 11 also reduced Ab 42 aggregation-induced cytotoxicity. When the dosage reached 8 mM, cell viability increased from 49% to 67%. In 2022, Gao innovatively combined post-translational modication (PTM) technology with POMs, rationally designed and synthesized a Wells-Dawson POM-based PTM agent POMD-TZ (thiazolidinethione as TZ) for chemical modication of amyloid peptides. 260 POMD-TZ could selectively bind to the Lys16 site, inhibit Ab aggregation, and reduce the cytotoxicity caused by the Ab peptide.

Liposomes
Liposomes have the advantages of non-toxicity, strong drugcarrying capacity, and ease of synthesis and modication, and have been widely used in the eld of drug delivery. 261,262 Gobbi et al. 263 reported that nanoliposomes containing phosphatidic acid (PA) and cardiolipin (CL) targeted aggregated forms of Ab 42 brils (22-60 nM) with high binding affinity. Mourtas et al. 240 successfully used click chemistry to decorate the surface of nanoliposomes with curcumin, and the curcumin-modied liposomes (maintaining the planarity) had extremely high affinity for Ab 42 bers (1-5 nM) and had sufficient stability for in vivo applications. This high-affinity binding may be due to a multivalent interaction between click curcumin liposomes and Ab. Taylor et al. 264 designed and formulated different types of nanosized liposomes incorporating or decorated with curcumin, a curcumin derivative, or lipid ligands (PA, CL, or GM1 ganglioside), and then evaluated their ability to inuence Ab 42 peptide aggregation based on ThT and a sandwich immunoassay. The results showed that the click-curcumin type was by far the most effective. Bana et al. 265 prepared phosphatidic acid and ApoE-derived peptide bi-functionalized mApoE-PA-LIP. mApoE-PA-LIP strongly bound the Ab peptide (kD = 0.6 mM), inhibited peptide aggregation and triggered preformed aggregates. The permeation rate across the BBB of mApoE-PA-LIP was 5-fold higher with respect to monofunctional liposomes. Papadia et al. 266 developed multifunctional LUV liposomes (mf-LIPs) having three ligands, one of which is a curcumin-lipid ligand (TREG) and the other two ligands target the transferrin and the LDL receptors of the BBB. Further research found that the multiple ligands of mf-LIPs did not interfere with each other, and mf-LIPs have multiple functions such as targeting the BBB and inhibiting amyloid aggregation. Meanwhile, in vivo experiments found that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by the liver and spleen. 267 Kuo et al. 268 designed a drug carrier system of ApoE-modied liposomes conjugated with PA. This system was used to improve BBB penetration and release quercetin (QU) and rosmarinic acid (RA) to inhibit Ab 42 . ApoE-QU-RA-PA-liposomes could penetrate the BBB because of strong attraction between low-density lipoprotein receptors and ApoE.

SiO 2
Silica nanostructures, due to their synthetic exibility, molecular properties, multifunctionality, and biocompatibility, have long been used in biomedical applications. 269,270 In 2016, Hulsemann et al. 241 reported a highly stable standard in the size range of native Ab oligomers consisted of a silica nanoparticle, which is functionalized with Ab peptides on its surface (Ab-SiNaP). The detection limit corresponded to an Ab concentration of 1.9 ng L −1 . Zhang et al. 271 synthesized b-NaYF 4 :Yb/Er@SiO 2 @RB by combining upconversion nanoparticles (UCNPs) with photosensitizers to disaggregate the preformed Ab aggregates under NIR light. UCNPs were able to transfer energy to RB at 980 nm and Ab 42 brils were disaggregated via photo-induced ROS. Jung et al. 30 designed Ab nanodepletors consisting of ultralarge mesoporous silica nanostructures and anti-Ab single-chain variable fragments (anti-Ab scFvs). The Ab nanodepletors suppressed Ab selfassembly, decreased the amount of Ab aggregates, and increased cell viability.
In addition, many other nanomaterials have been reported for AD diagnosis and treatment, such as carbon nanospheres, hydrogen-bonded organic frameworks (HOFs), polystyrene nanoparticles and so on. Ma et al. 272 designed NIR-II photothermally responsive mesoporous carbon nanospheres KD8@N-MCNs. The graphitic N dopants introduced abundant electrons into the p* orbital between the HOMO and LUMO gaps, thus enhancing the light absorption properties. Under 1064 nm light irradiation, the nanospheres disaggregated Ab 42 aggregates because of photothermal conversion ability. Meanwhile, KD8@N-MCNs alleviated oxidative stress due to the SOD and CAT enzymatic activities. Due to the covalently graed KLVFFAED, KD8@N-MCNs could cross the BBB and specically recognize Ab 42 aggregates. HOF materials exhibit considerable biocompatibility and low toxicity attributed to their metal-free nature, thus being an excellent candidate for drug delivery and biological applications. 273 Zhang et al. designed a twophoton NIR-II-activated photooxygenation catalyst DSM@n-HOF-6 (DSM = 4-[p-(dimethylamino) styryl]-1methylpyridinium).
TCPP(meso-tetrakis(carboxy phenyl) porphyrin) was periodically incorporated into HOFs, while the targeting peptide KLVFFAED (KD8) was conjugated to DSM@n-HOF-6 (DSM@n-HOF-6@KD8). 274 The up-conversion uorescence of DSM could be absorbed by TCPP to generate 1 O 2 for Ab oxygenation, and DSM@n-HOF-6@KD8 could inhibit the brillation of Ab monomers and reduce the cytotoxicity of Ab by photooxygenation. The application of polystyrene nanoparticles and upconverting nanoparticles in amyloid diseases has also been reported. 275,276 Many nanomaterials have been reported for AD diagnosis and treatment. Targeting issues and the interaction between nanomaterials and peptides are the main issues that need to be considered. At the same time, issues such as inhibition efficiency, reversibility of brosis, and nanoparticle metabolism also need to be considered.

Conclusions and outlook
Due to the intensication of the aging of the population, neurodegenerative diseases, especially AD, have become one of the most serious obstacles to social development. This review comprehensively summarized the recent research for modulating amyloid aggregation associated with neurodegenerative diseases, including AD based on nanomaterials and nanotechnology. In this review, nanomaterials exhibited multiple roles in the treatment of AD. Firstly, nanomaterials can directly interact with Ab peptides and accelerate or slow down amyloid aggregation. Secondly, as nanocarriers, nanomaterials can also be used to load various drugs and assist drugs to across the BBB and inhibit amyloid. In addition, nanomaterials and drugs can synergistically resist a series of problems arising from amyloid aggregation. Moreover, some advanced nanomaterials with photosensitivity can strongly affect amyloid aggregation through PTT or PDT. 277 Multiple interaction mechanisms such as electrostatic interaction, hydrophobic interaction, p-p stacking, and metal ion chelation are the main reasons for amyloid brillation, and taking advantage of these interactions in the design process and application process, nanomaterials can effectively adsorb amyloids on their surface and block the amyloid aggregation. As novel treatment methods, advanced nanomaterials with the function of PTT and PDT have the advantages of accuracy, ease of administration, high efficiency, and few side effects. In PDT treatment, nanomaterials can generate ROS and oxidize the amino acid residue of amyloid, and then the aggregation process of amyloid is inhibited. In PTT treatment, because the amyloid formation is highly dependent on temperature, the change of localized temperature can affect amyloid aggregation. Currently, PDT and PTT have attracted more and more attention from researchers, and these methods may be the focus of follow-up research. In the future, a deep and comprehensive understanding of the functional design of nanomaterials and the properties of these nanomaterials is still necessary. The mechanism of action of nanomaterials in AD treatment, especially the in-depth research mechanism of amyloid, including interaction and photoinhibition process, also needs to be further explored. From the current point of view, the development of nanomaterials has shown a new chapter in the treatment of AD.
Regarding the application of nanomaterials for inhibiting amyloid, there are several aspects to note: (1) in order to successfully achieve clinical applications, it is necessary to further understand and explore the in vivo distribution and metabolism of nanomaterials. In future research, it is necessary to continue in-depth research on the biological properties, preparation processes, and surface modication of nanomaterials to achieve a more safe and more efficient inhibition of amyloid aggregation and disaggregation of amyloid brils. (2) The BBB permeability of nanomaterials can be improved through some conjugates such as transferrin (via transferrin receptor-mediated endocytosis to cross the BBB), and transiently disrupting the blood-brain barrier by physical methods such as photothermal and intranasal administration may also be an effective method. (3) To predict the interactions between amyloid/brils and nanoparticles in advance, it is also necessary to build suitable computational models and deeply explore how amyloid/brils and nanoparticles interact. (4) Most nanomaterials interact with amyloid through non-covalent interactions, which are weak and may cause reversible aggregation/ disaggregation processes, and covalent modulators can prolong their duration of action. PDT and PTT also can directly irreversibly modulate the amyloid brosis process. (5) The role of nanomaterials and amyloid at the cellular level and in vivo is worth further research in the future, which will provide a strong basis for a biological experiment for nanomaterials to transform nanomedicines. (6) For precise inhibition, the problem of targeting needs to be solved urgently. Targeting ligands have been introduced, such as antibodies, peptides, and aptamers. The amyloid targeting ligand may lose or weaken its binding affinity to amyloid during PDT or PTT, so it is crucial to develop targeting ligands with high stability and strong affinity under harsh conditions. (7) Many studies have pointed to oligomers, and the subsequent application of nanomaterials in oligomers will become the focus and be further explored. (8) Although studies have shown that nanomaterials have a good inhibition efficiency in vitro, the inhibition efficiency needs to be further improved in vivo. To prove whether the addition of nanomaterials can restore the normal function of nerve cells, various experiments in vivo including clinical research still need to be carried out.

Conflicts of interest
The authors declare no conict of interest.