Targeting protein aggregation: the promising application of polyoxometalates in neurodegenerative diseases

Abstract

With the global aging trend, the incidence of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has greatly increased. NDDs are sporadic and rare inherited diseases of the nervous system characterized by loss of neurons and slow progressive degeneration in different regions of the nervous system. A common feature of many NDDs is the formation of persistent and irreversible protein aggregates during their pathogenesis, such as amyloid β (Aβ) and tau aggregates in AD, α-synuclein aggregates in PD and TDP-43 aggregates in ALS. Hence, therapeutic approaches aiming to inhibit the formation or promote the clearance of protein aggregates have emerged in recent years, some of which have advanced to clinical trials. Polyoxometalates (POMs), formed by the condensation reaction of early transition-metal oxo anions, are prime candidates for constructing functional nanoclusters covering a wide range of fields including catalysis, energy storage and biomedicine. A series of modified POMs obtained by high-throughput screening or rational design are able to modulate protein aggregation via stereoselectivity. Here we summarize and discuss recent progress in the therapeutic applications of POMs to target protein aggregation in NDDs.

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1. Introduction

Polyoxometalates (POMs) are a class of metal–oxo clusters formed by discrete early transition metals, M (such as V, Mo, W, Nb, Sb, etc.), and oxygen in their highest oxidation states.¹ Since 1934, scholars have classified POMs mainly as six basic structures, Keggin (XM₁₂O₄₀ⁿ⁻), Dawson (X₂M₁₈O₆₂ⁿ⁻), Anderson (XM₆O₂₄ⁿ⁻), Waugh (XM₉O₃₂ⁿ⁻), Silverton (XM₁₂O₄₂¹⁰⁻) and Lindqvist (M₆O₁₉²⁻) (X = Si, P^V, B, Ge, As^V, Al, etc.; M = V, Mo, W, Nb, Sb, etc.) (Fig. 1a–c).² Among these structural formulas, “X” refers to heteroatoms, also known as central atoms. POMs contain the following characteristics. Firstly, POMs are relatively stable, with strong electron acceptance and transfer abilities, and can form derivatives of different structures by coupling with metal cations or organic groups.³ Secondly, POMs have excellent redox properties. Thirdly, POMs are easily soluble in water and have relatively high thermal stability. Therefore, the unique properties of POMs enable them to exhibit diversity in terms of size, structure, and physicochemical capabilities. POMs and their functionalized materials have broad application prospects in cutting-edge technology fields such as biomedicine, photomagnetic systems, environmental protection, catalysts and energy storage.^4–7

Fig. 1 Overview of POMs with the most common archetypes. (a) Wells–Dawson structure; (b) Keggin structure; (c) Anderson structure.

In the past few decades, POMs have been found to possess anti-tumor, antiviral and antibacterial activities and exhibit therapeutic potential in the treatment of cancer and infectious diseases as a new generation of inorganic metal drugs.^8–10 In 1974, Jasmin et al. first found that (NH₄)₁₇Na[NaSb₉W₂₁O₈₆] had an inhibitory effect on tumors caused by viruses.¹¹ Since then, the development of the bioactivity of POMs has attracted considerable attention, and many POM derivatives have been synthesized. Firstly, POMs can be used as a photosensitizer to promote apoptosis of tumor cells by photothermal therapy (PTT), which can induce local irreversible damage to the tumor cell membrane within a short period of time.^12,13 In 2024, Tang et al. designed and synthesized POM-nanozyme-integrated nanomotors (POMotors) based on P₂W₁₈Fe₄ and polydopamine (PDA).¹⁴ The tumor inhibition rate of POMotors reached 93.86% after 10 min of near infrared (NIR) irradiation at 808 nm, which significantly improved the therapeutic effect of PTT on tumor growth. Secondly, POMs can also be used in chemodynamic therapy (CDT) to inhibit tumor growth by depleting glutathione and converting endogenous H₂O₂ into OH, which is harmful to tumor cells.^15,16 In 2024, Ge et al. synthesized Mn-POM-based single-atom catalysts (Mn-POM-SACs), anchoring the SACs firmly on the POM supports through oxygen atom coordination.¹⁷ Mn-POM-SACs exhibited outstanding catalytic activities (e.g. peroxidase-like, oxidase-like, catalase-like, and glutathione peroxidase-like activities), which produced cytotoxic ROS and depleted glutathione for cancer therapy. In addition, the redox nature of POMs reduces inflammation by eliminating inflammation-related reactive oxygen species (ROS).¹⁸ Thirdly, POMs have demonstrated potent antiviral effects against various viruses, including human immunodeficiency virus, herpes simplex virus, dengue virus, and influenza virus.¹⁹ As early as 2020, Qi et al. discovered that Keggin-type Cs₂K₄Na[SiW₉Nb₃O₄₀] (POM-12) could inhibit the infection of Flaviviridae viruses due to destruction of the viral envelope, which disrupted the integrity of the viruses and promoted the RNA genome of viral particles being easily degraded by RNase.⁹ Finally, recent studies have also demonstrated that Mo-POMs exhibit highly effective anti-biofilm and bactericidal properties.²⁰ In 2023, Qu et al. synthesized Mo-POM nanoclusters doped with Cu (Cu-POM NCs) as an efficient bioorthogonal catalyst.²¹ Through the biofilm-responsive self-assembly behavior, Cu-POM NCs facilitated the efficient synthesis of antibacterial molecules and PTT selectively triggered by H₂S in pathogens, which is beneficial for the inhibition of bacterial tolerance and elimination of biofilms. However, the applications of POMs and their derivatives are not limited to cancer and infectious diseases. Recent studies have uncovered the novel bioactivities of POMs and extended their applications to the treatment of neurodegenerative diseases (NDDs).²²

A typical example of NDDs linked with the therapeutic potential of POMs is Alzheimer's disease (AD), which is marked by the aggregation of β-amyloid (Aβ). The interaction of POMs with Aβ is closely related to the structure, volume and electrostatic attraction of POMs.²³ Interestingly, due to the tunability of the POM structure, different types of metals as well as organic or inorganic groups can be easily introduced into POMs. Therefore, a variety of functional POM compounds have been synthesized to reduce their toxicity and improve their biological activity. For an up to date and excellent review on the therapeutic application of POMs for combating Aβ aggregation in AD, as well as correlations between anti-amyloid activities and structural features of POMs, refer to Ma et al.²⁴

In addition to AD, many other NDDs are also associated with the formation of persistent and irreversible protein aggregates. Accordingly, POMs have common application potential in various NDDs by targeting and modulating different protein aggregates. In this review, we summarized various types of POM-based nanomaterials with well-defined structures as therapeutic candidates for NDDs, including AD, prion disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). We hope that this review will be beneficial for understanding the relationship between POM structures and their anti-NDD properties, and provide implications for the design and precise synthesis of POM-based drug candidates for NDD treatment.

2. NDDs and pathogenic protein aggregates

With the global aging trend, the prevalence of NDDs is increasing.²⁵ NDDs are caused by the loss of neurons and the myelin sheath and worsen over time, leading to structural damage and dysfunction of the nervous system. Studies have found that NDDs are related to oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis and other pathophysiological changes.²⁶ Recently, studies have shown that misfolding, aggregation and accumulation of proteins in neurons are at the center of the pathogenesis of NDDs (Fig. 2), such as AD, PD, ALS, and etc.^27,28

Fig. 2 NDDs and pathogenic protein aggregates. NDD-associated proteins form fibrils that aggregate in neurons through a range of secondary mechanisms, including oxidative stress and neuroinflammation, eventually leading to neuronal death.

2.1. AD

2.1.1. Aβ amyloid aggregation associated with AD. AD is an age-related neurodegenerative disease with cognitive decline and impaired functioning that affects personal every day and social activities.²⁹ It is estimated that AD accounts for 60 to 80% of all dementia cases. Most patients exhibit late-onset AD, and only 5% of patients inherit the condition and exhibit early onset AD between the ages of 30 and 60.³⁰ The main pathological features of AD are characterized by Aβ-containing extracellular plaques and tau-containing intracellular neurofibrillary tangles.^31,32 Aβ is a series of small peptide isoforms ranging from 38 to 43 amino acids, which are cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase (Fig. 3).^33,34 Among all Aβ isoforms, Aβ40 and Aβ42 are the most important ones that form Aβ aggregates, with Aβ42 bearing two extra residues at the C-terminus compared to Aβ40. Aβ usually exists as a stable monomer in the normal physiological state, but forms multimers and ultimately amyloid fibrils consisting of β-sheet structures in the pathological state.^35,36 According to the amyloid hypothesis, mutations in genes involved in Aβ biosynthesis, aggregation and degradation could lead to an imbalance between Aβ production and clearance, which further results in abnormal accumulation of Aβ aggregates in the brain.³⁷ The N- and C-termini of Aβ, His13–Lys16 (HHQK), hinge or turning region and hydrophobic region (KLVFF) play key roles in Aβ oligomeric and fiber propagation.³⁸ Therefore, diverse strategies aimed at mitigating Aβ-induced neurotoxicity have been proposed for the treatment of AD_.²³

Fig. 3 Aβ polypeptide is produced from APP though stepwise cleavage by secretases.

2.1.2. S100A9 amyloid aggregation associated with AD. Neuroinflammation, which is defined as activation of the innate immune system typically within the brain or spinal cord, has been demonstrated as a major driver of multiple NDDs, including AD and ALS.^39,40 The pro-inflammatory S100A9 protein contributes significantly to the amyloid-neuroinflammatory cascade in NDDs.⁴¹ S100A9 is a member of the calcium-binding protein and S100 protein family. Stimulation of inflammatory signaling pathways by S100A9 has been found in many diseases related to inflammatory processes.⁴² Overexpression of S100A9 is closely associated with neuronal death and the formation of Aβ amyloid.⁴³ Currently, studies have found that S100A9 itself is highly neurotoxic, causing rapid neuronal damage and death. S100A9 amyloid aggregates are more stable and more resistant to proteases, which are unfavorable for clearance. As a result, S100A9 interacts with Aβ to promote the formation of fibrillar amyloid β structures, completing the vicious cycle of the amyloid-neuroinflammatory cascade.⁴⁴

2.2 Prion disease

Prion disease is a rare neurodegenerative disease in humans and animals caused by the misfolding and aggregation of prion protein (PrP).⁴⁵ PrP has two major isoforms: the normal cellular prion protein (PrP^c) and the pathogenic scrapie prion protein (PrP^Sc).⁴⁶ PrP^c is a soluble glycoprotein that is very sensitive to protease digestion. PrP^c contains an N-terminal flexible tail and a globular C-terminal structural domain that includes a low content of β-sheet structures (3%) and three α-helices.⁴⁷ In contrast, PrP^Sc is the main component of prions characterized by resistance to protease digestion, insolubility and high levels of β-sheet structure.⁴⁸ During the pathogenesis of prion disease, PrP^c is conformationally transformed into PrP^Sc, which in turn acts as an infectious template that recruits PrP^c for conformational conversion.⁴⁹ Therefore, the inhibition or clearance of pathogenic PrP^Sc aggregates is of particular significance to the treatment of prion disease.

2.3 PD

The typical motor features of PD include bradykinesia, rigidity, resting tremor and postural instability due to impaired activity in the basal ganglia caused by the loss of dopaminergic neurons in the substantia nigra (SN).⁵⁰ However, patients often exhibit a variety of non-motor symptoms, including constipation, hypotension, rapid eye movements, sleep disturbances and cognitive impairment.⁵¹ The neuronal protein α-synuclein encoded by the SNCA gene plays an important role in PD.⁵² Of the major PD-causative gene mutations, six have been identified in the SNCA gene, namely, A53T, A30P, E46K, H50Q, G51D and A53E.⁵³ α-Synuclein interacts with a variety of proteins to perform many functions, such as regulation of phospholipase D and tyrosine hydroxylase. However, when α-synuclein is mutated, it is prone to misfold and form neurotoxic protein aggregates in the brain.⁵⁴

2.4 ALS

ALS is a type of NDD with progressive muscle weakness resulting from the loss of upper and lower motor neurons.⁵⁵ ALS patients eventually die due to respiratory failure. Approximately 10% of ALS cases are inherited in families, and 90% of ALS cases are sporadic with uncertain etiology. Known disease-causative mutations have been identified in 15% of ALS cases.⁵⁶ Many of these mutations occur in genes encoding RNA binding proteins, such as TDP-43 and FUS. Mutated TDP-43 and FUS proteins found in ALS patients are prone to form protein aggregates via a process known as liquid–liquid phase separation (LLPS).⁵⁷ It has been shown that TDP-43 and FUS are key components of insoluble aggregates in patient brains. TDP-43 and FUS are mainly localized in the nucleus to exert their functions such as regulation of splicing and stabilization of RNA. However, mutated TDP-43 and FUS proteins are retained in the cytoplasm and further result in the formation of neurotoxic protein aggregates as the concentration of cytoplasmic proteins increases.^58–60 Both the loss of their original functions in the nucleus and the gain of neurotoxic functions in the cytoplasm contribute to neuronal death in ALS.⁶¹

Recent studies have shown that POMs are potential candidates for the treatment of AD due to their low toxicity and therapeutic activity.⁶² A series of POMs and transition metal functionalized POM derivatives have been reported as inhibitors of Aβ protein aggregation. Next, we focus on the current progress of POMs with therapeutic potential in AD and prion disease (Table 1), as well as the future prospects of POMs in PD and ALS.

Table 1 Summary of POMs that target NDDs

Category	Neurodegenerative disease	Protein aggregates	POMs	Molecular mechanism	Ref.
1	AD	Aβ	K8[P2CoW17O61]	K8[P2CoW17O61] can act as a photocatalyst for Aβ monomers and oligomers to inhibit Aβ-induced toxicity	64, 75 and 82
2	AD	Aβ	α-Na9H[SiW9O34], K8[P2CoW17O61], K7[PTi2W10O40], K8[β-SiW11O39]	Interactions between the large surface of POMs and Aβ oligomers may inhibit the formation of Aβ fibrils by blocking direct contact between Aβ monomers	64
3	AD	Aβ	(NH4)42{Mo132O372(OAc)30}	Due to their polyanionic nature and rigid cagelike structures, Zn^2+ and Cu^2+ are able to strongly interact with (NH4)42{Mo132O372(OAc)30}, which inhibits metal-ion-induced aggregation of Aβ	74
4	AD	Aβ	K8[P2NiW17O61], K8[P2CuW17O61]	Electrostatic and histidine-chelating effects promote strong binding between POMds and Aβ monomers, significantly inhibiting Aβ aggregation	82
5	AD	Aβ	[MnMo9]-D-Phe, [MnMo9]-L-Phe	Firstly, chiral POMs can bind to the cationic cluster from His13 to Lys16 (HHQK). Secondly, Leu17 and Val18 on Aβ can interact with hydrocarbon chains. Thirdly, two adjacent phenylalanine residues (F19 and F20) form a strong hydrophobic region and specifically interact with hydrophobic amino acids. Finally, chiral POMs bind to the Aβ13–23 segment and exhibit strong enantioselectivity in inhibiting Aβ aggregation	76
6	AD	Aβ	[(CH3)2NH2]15{α-P2W15Zr3(L-tartH)[α-P2W16]}	Chiral POMs selectively inhibit Aβ aggregation, and in terms of inhibitory activity, D-POMs are significantly higher than L-POMs	84
7	AD	Aβ	[CoL(H2O)]2[CoL]2[HAs^VMo^V6Mo^VI6O40]	CAM can disassemble β-sheet-rich fibrils and metal-induced or self-assembled Aβ aggregates, and further inhibit ROS. Thus, it could protect neurons from synaptic toxicity caused by metal-induced Aβ aggregates	66
8	AD	Aβ	(Me4N)3{PW11(SiC3H6NH2)2PtCl2}	Inhibition of Aβ aggregation by Pt^II–PW11 is attributed to multiple interactions, including coordination interactions between Pt^2+ and amino acids, electrostatic interactions, hydrogen bonding and van der Waals forces	38
9	AD	Aβ	POM@peptide	Due to the relatively large size of POM@peptide, its binding site would cover the N-terminal hydrophobic segment of Aβ monomers. Therefore, POM@peptide can inhibit the formation of Aβ aggregates	85
10	AD	Aβ	AuNPs@POMD-8pep	AuNPs@POMD-8pep has protease-like activity to deplete Aβ aggregation and superoxide dismutase (SOD)-like activity to scavenge Aβ-induced ROS	86
11	AD	Aβ	CeONP@POMs	CeONP@POMs have proteolytic enzyme activity. When binding to Aβ fibrils, the stability of Aβ fibrils is reduced and they are decomposed into oligomers or monomers. Then, Aβ monomers can be hydrolyzed by CeONP@POMs	87
12	AD	Aβ	rPOMDs@MSNs@copolymers	Due to their strong NIR absorption, rPOMDs@MSNs@copolymers are capable of generating local hyperthermia under NIR laser irradiation. Furthermore, rPOMDs@MSNs@copolymers are capable of scavenging Aβ-induced ROS	88
13	AD	Aβ	(H2dap)6[Cd4Cl2(B-α-AsW9O34)2]·8H2O	(H2dap)6[Cd4Cl2(B-α-AsW9O34)2]·8H2O can efficiently modulate the β-sheet-rich fibrils of Aβ and inhibit the production of ROS from Aβ aggregates	89
14	AD	Aβ	K8{[Co(H2O)4][HP2Mo5O23]2}·8H2O	As a conformational modulator, K8{[Co(H2O)4][HP2Mo5O23]2}·8H2O can prevent Aβ aggregation and suppress the generation of ROS	90
15	AD	Aβ	AuNPs@POM@PEG	The synergetic effect between AuNPs and POMs effectively inhibits Aβ aggregation	17
16	AD	Aβ	Peptide@Mo-POMs	Peptide@Mo-POMs can suppress Zn^2+-induced Aβ aggregation and disaggregate Aβ fibrils	91
17	AD	S100A9	[N(CH3)4]6[Nb10O28], [N(CH3)4]7[TiNb9O28]	Both POMs interact with positively charged Lys-rich regions on the surface of S100A9	41
18	Prion disease	PrP^Sc	H4[PW12O40]	Separation of PrP^Sc from PrP^C is achieved by precipitation with H4[PW12O40]	92
19	Prion disease	PrP^Sc	Na4[SiW12O40], K5[BW12O40], Na6[H2W12O40]	Size-specific electrostatic interactions between Keggin POMs and multiple PrP^Sc oligomers lead to PrP^Sc deposition	93
20	Prion disease	PrP^Sc	(NH4)6[H2W12O40], K5[BW12O40]	BTA and HTA can significantly reduce the number of amyloid fibrils; this is associated with an increased negative charge of POMs	94
21	Prion disease	PrP^Sc	Na7[PW11O39]·12H2O	Na7[PW11O39]·12H2O can selectively bind to PrP^Scvia electrostatic interactions	95
22	Prion disease	PrP^Sc	Ag3PW12O40	As a Keggin-type POM, Ag3PW12O40 can specifically interact with PrP^Sc to inhibit its formation	96
23	Prion disease	PrP^Sc	[PW11VO40]^4−, [PW10V2O40]^5−, [PMo11VO40]^4−, [PMo10V2O40]^5−	[PW10V2O40]^5− shows the strongest oxidation effect on the Met residue of PrP^Sc	97

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3. Application of POMs in AD via targeting Aβ

As a class of metal–oxo clusters (MOCs), POMs have shown good application prospects in biomedicine since 1998.⁶³ The molecular properties of POMs affecting recognition and reactivity with their biomolecular targets are variable, including polarity, redox potential, surface charge distribution, shape and acidity.⁶⁴ Recent studies have shown that POMs can restrain Aβ aggregation to reduce Aβ-induced cytotoxicity through non-covalent interactions such as hydrogen bonding, electrostatic attraction, π–π stacking and hydrophobic interactions.⁶⁵ At the same time, POMs can cross the blood–brain barrier (BBB) and be metabolized within a period of time; this provides a novel strategy for intervening in the pathology of AD.⁶⁶ In recent years, countless potential drugs have demonstrated low efficacy in clinical trials due to their inability to penetrate the BBB, which becomes a significant challenge in drug development for neurological disorders.⁶⁷ The BBB is a dynamic, semipermeable, and highly selective system located in the brain microvasculature of most vertebrates. Its primary function is to separate the blood from the extracellular fluid of the brain, which plays a crucial role in regulating the transport of substances essential for proper brain function.⁶⁸ The transmission pathways of the BBB mainly involve diffusional transmission, the transporter protein pathway, receptor-mediated transcytosis, adsorptive transcytosis and the cell-mediated pathway. POMs mainly cross the BBB through adsorptive transcytosis, which relies on electrostatic interactions with the surface of the cell membrane.⁶⁹ Additionally, the easily adjustable and structurally variable nature of POMs enables diverse modifications, such as chirality, nanocarriers, and liposomes, which can further enhance the penetration ability of POMs.^70,71 For example, in 2023, Perich et al. combined AuNPs, PEG and POMs to synthesize AuNPs@POM@PEG for the treatment of AD.⁷² PEG can improve biocompatibility by reducing BBB damage and protein absorption. In addition, the drug nanocarrier AuNPs with a smaller size and targeting molecule modification can more easily pass through the BBB, further promoting the absorption of POMs.⁷³ Therefore, more and more attention has been paid to the applications of POMs and their derivatives in the treatment of AD.

3.1. Pure POMs

Pure POMs exhibit rich chemical compositions and nanostructures.⁷⁴ Studies have shown that polyoxytungstates (POTs), polyoxymolybdates (POMos), polyoxyvanadates (POVs) and polyoxoniobates (PONbs) are able to inhibit protein aggregation.^64,74–79 In 2011, Qu's group demonstrated for the first time that the Wells–Dawson structure of POMs could effectively inhibit Aβ aggregation.⁶⁴ This finding also proved that phosphotungstate with the Wells–Dawson structure had the highest inhibitory effect and a POM with the Keggin structure had a moderate to high inhibitory effect on Aβ aggregation, while a smaller POM with an Anderson structure showed no effect, suggesting that the POM–Aβ interaction mainly relied on size-dependent electrostatic interactions.²⁴ In 2014, Chen et al. synthesized three representative POM nanoclusters based on Mo₁₃₂ for countering Aβ40 aggregation (Fig. 4).⁷⁴ Recent studies found that POMs carrying a large amount of negative charges preferentially bound to the positively charged Lys and Arg residues on the Aβ protein surface.⁶⁵ For example, the Aβ12–28 fragment is positively charged with a cationic His13–Lys16 (HHQK) cluster. In addition, POMs can bind to Aβ monomers and inhibit the formation of their aggregates by electrostatic attraction.³⁸ In 2022, Gao et al. modified a Wells–Dawson structured POM with thiazolidinethione (POMD-TZ) to improve the binding specificity to the Lys side chain of Aβ.⁷⁷ POMD-TZ could selectively covalently bind to the Lys16 site on Aβ and reduce amyloid aggregation via site-directed chemical modification (Fig. 5). In conclusion, the size, surface charge and ligands of POM complexes may play important roles in Aβ recognition and inhibition of amyloid aggregation.⁷⁴ It also raises the question of the necessity for POM modification for better recognition and inhibition of Aβ aggregation.

Fig. 4 The basic spherical shape of anionic clusters.

Fig. 5 POMD-TZ can specifically modify Aβ at the Lys16 site and inhibit Aβ aggregation.

3.2. Modified POMs

3.2.1. Transition metal hybrid POMs. As drug candidates, pure POMs are limited by cytotoxicity and instability, which may restrict their applications in vivo.⁸⁰ Therefore, researchers started to search for more suitable inhibitors or functionalized POMs, and further explored their biological mechanisms and theories.⁸¹ In 2014, Qu's group designed and synthesized a series of transition metal functionalized POMs with an improved inhibitory effect on Aβ aggregation compared to Wells–Dawson type POMs (Fig. 6a).⁸² They found that the order of inhibitory effects followed the trend of POMds (Dawson type POM derivatives)-Dawson-Ni > POMds-Dawson-Co > POM-Dawson. The inhibition of nickel metallized POM derivatives achieved sixfold improvement. Indeed, the surface negative charge densities of POMs are controlled by multiple factors, including a redox active metal, transition metal substitution, charge density and geometry, which are closely related to the binding between POMs and Aβ.⁸³ The POMds-binding site in Aβ was the cationic HHQK cluster, rather than His or another single amino acid. POM-Dawson contained six negative charges, while POMds had eight negative charges so that the electrostatic attraction to the cationic HHQK clusters was increased (Fig. 7).⁸² In addition, POMds-Dawson-Ni and POMds-Dawson-Co showed better inhibition of Aβ-mediated peroxidase-like activity, suggesting that the modified POMs could be used as bifunctional drugs against AD. Meanwhile, the POM-binding site in Aβ12–28 was a positively charged cavity-like domain mainly surrounded by the amino acids His13, Gln15 and Lys16.⁷⁶ Through histidine chelation between transition metals and cationic HHQK clusters, POMds strongly bound to Aβ monomers, which prevented direct contact between Aβ monomers to restrain their nucleation and fiber growth (Fig. 8).⁸² Through electrostatic attraction and histidine chelation, POMs and their derivatives can more effectively target Aβ protein to prevent aggregation.

Fig. 6 Structures of transition metal hybrid POMs. (a) Wells–Dawson structure and Wells–Dawson POMds with defined histidine-chelating metals (such as Ni, Co, Cu, Fe and Mn). (b) Polyhedral/ball-and-stick representation of (H₂dap)₆[Cd₄Cl₂(B-α-AsW₉O₃₄)₂]·8H₂O. (c) A combined polyhedral/ball-and-stick representation of K₈{[Co(H₂O)₄][HP₂Mo₅O₂₃]₂}·8H₂O. (PO₄ polyhedra: light orange; WO₆ polyhedra: teal; MoO₆ octahedra: violet; AsO₄: yellow; the histidine-chelating metal is shown as a purple ball. The Cd, Cl, O, C, N and H atoms are shown as dark blue, light green, red, grey, dark blue and white balls, respectively.)

Fig. 7 POMds can inhibit Aβ aggregation by binding to the cationic HHQK clusters on Aβ monomers through electrostatic interactions. Compared to POMs-Dawson, which contains six negative charges, POMds have eight negative charges to increase the electrostatic attraction to the HHQK site.

Fig. 8 POMds strongly bind to Aβ monomers by histidine chelation between transition metals and cationic HHQK clusters.

Photocatalysis is a low cost, high efficiency and energy saving technology. As a novel type of photocatalyst, POMs have broad application prospects related to photocatalysis, including the treatment of AD.⁹⁸ In 2013, Li et al. discovered that K₈[P₂CoW₁₇O₆₁] had unparalleled photosensitive properties.⁷⁵ When generating ROS through UV excitation, POMs could serve as photocatalysts to weaken hydrogen bonds between amino acid residues. Thus, the secondary structure of the Aβ peptide was disrupted, and the α-helix configuration was lost. Therefore, POMs could degrade Aβ monomers and oligomers and block Aβ-induced cytotoxicity by photocatalysis.⁹⁹

Misfolded protein accumulation is a critical step involved in the onset and progression of AD.¹⁰⁰ The basic structure of the toxic substance is β-sheet Aβ aggregates formed by a process of misfolded aggregation. Furthermore, ROS generated by toxic aggregates is a crucial neurodegenerative factor. In 2022, Hua et al. successfully designed and synthesized a nano-POM, (H₂dap)₆[Cd₄Cl₂(B-α-AsW₉O₃₄)₂]·8H₂O (dap = 1,2-diaminopropane), based on a tetra-Cd cluster sandwiched by a trivacant Keggin type tungstoarsenate (Fig. 6b).⁸⁹ It could both modulate the β-sheet-rich fibrils of Aβ peptides efficiently and inhibit the production of ROS from Aβ aggregates to relieve the neurotoxicity of Aβ aggregates.

In recent work, a POM based on a {Co(H₂O)₄}²⁺ complex and two Strandberg-type fragments, [P₂Mo₅O₂₃]⁶⁻, sandwich-type K₈{[Co(H₂O)₄][HP₂Mo₅O₂₃]₂}·8H₂O (abbreviated as CoPM), was synthesized and structurally characterized (Fig. 6c).⁹⁰ Because POM fragments and Co complexes interact synergistically, CoPM could modulate the conformation. As a conformational modulator, CoPM could prevent Aβ from aggregating and prevent Cu²⁺–Aβ species from producing ROS.

3.2.2. Ligand-modified POMs.
3.2.2.1. Chiral ligands. New possibilities for POMs in the field of biomedicine are constantly being developing as the properties of POMs are different from other inorganic compounds in various aspects, e.g. chirality. Chirality is a basic feature of nature. The basic substances that constitute living organisms are chiral, such as amino acids, sugars, proteins, DNA, etc.¹⁰¹ Molecules containing asymmetric carbon substitutions are called chiral molecules.¹⁰² Chiral drugs are also a kind of common chiral molecule. Chiral POMs are a class of chiral cluster molecules with precise asymmetric structures. By combining their advantages with chirality, POMs have been widely used in stereoselective catalysis, chiral recognition, sensing, biological simulations, nonlinear materials and biomedicine.^103,104 Aβ consists of an α-helix/β-sheet structure, which is sensitive to the chiral environment. Therefore, chiral recognition plays a crucial role in the recognition and inhibition of Aβ aggregation.¹⁰⁵ In 2019, Gao et al. synthesized a series of POMs functionalized with chiral amino acids, including negatively charged amino acids (D-glutamic acid and L-glutamic acid), positively charged amino acids (D-histidine and L-histidine), and hydrophobic amino acids (D-leucine, L-leucine, D-phenylalanine, and L-phenylalanine) (Fig. 9a).⁷⁶ Subsequently, these chiral POMs were screened based on binding affinity and enantioselectivity to Aβ. They found that POMs modified with D-phenylalanine (POM-D-Phe) interacted with two hydrophobic amino acids (Phe4 and Phe19) in Aβ1–40 to form a strongly hydrophobic region, leading to inhibition of Aβ aggregation by a specific hydrophobic amino acid interaction. Compared with POMs-L-Phe, POMs-D-Phe formed two additional hydrogen bonds with Aβ located at Ser8 and His13.

Fig. 9 Structures of ligand modified POMs. (a) Rationally designed D/L-amino acid-functionalized POM derivatives. (b) The polyhedral/ball-and-stick representation of [(CH₃)₂NH₂]₁₅{[α-P₂W₁₅O₅₅(H₂O)]Zr₃(μ₃-O)(H₂O)(L/D-tartH)[α-P₂W₁₆O₅₉]}. (c) The polyhedral/ball-and-stick representation of [CoL(H₂O)]₂[CoL]₂[HAs^VMo^V₆Mo^VI₆O₄₀] monomer. (d) The polyhedral/ball-and-stick representation of (Me₄N)₃[PW₁₁O₄₀(SiC₃H₆NH₂)₂PtCl₂] (MoO₆ octahedra: violet; MnO₆ polyhedra: dark yellow; PO₄ polyhedra: light orange; WO₆ polyhedra: teal. The Zr, Co, Si, Pt, Cl, O, C and N atoms are shown as green, pink, plum, purple, light green, red, grey and dark blue, respectively).

Given the critical influence of chirality on Aβ aggregation, incorporating enantioselective recognition into POMs is a reasonable modification during the design of Aβ inhibitors. Recently, Hu et al. prepared a couple of inherently enantiomerically pure POMs, [(CH₃)₂NH₂]₁₅{[α-P₂W₁₅O₅₅(H₂O)]Zr₃(μ₃-O)(H₂O)(L-tartH)[α-P₂W₁₆O₅₉]} (L-POM) and [(CH₃)₂NH₂]₁₅{[α-P₂W₁₅O₅₅(H₂O)]Zr₃(μ₃-O)(H₂O)(D-tartH)[α-P₂W₁₆O₅₉]} (D-POM), as novel chiral Aβ inhibitors (Fig. 9b).⁸⁴ Owing to their chiral conformation and similar size to typical α-helix peptides, the chiral POM enantiomers exhibited a different binding affinity with Aβ40, leading to a noticeable enantioselective inhibitory effect on Aβ40 aggregation. In contrast to L-POM, D-POM displayed a higher Aβ40-binding affinity and greater brain biodistribution. D-POM had the ability to significantly reduce Aβ40 accumulation, scavenge ROS and rescue memory deficits in a mouse model of AD. Therefore, chiral POMs have improved enantioselectivity and specificity for their chiral biological targets and are promising modified POMs for the recognition of Aβ protein for AD diagnosis and treatment.

3.2.2.2. Other ligands. In 2018, Ma et al. designed a modified POM, [CoL(H₂O)]₂[CoL]₂[HAs^VMo^V₆Mo^VI₆O₄₀] [CAM, L = 2-(1H-pyrazole-3-yl)pyridine], to decompose Aβ aggregates, with L as the Aβ targeting group and POM as the conformational modifier (Fig. 9c).⁶⁶ X-ray crystallography showed that CAM consisted of an ε-Keggin unit and four coordination units. CAM could disaggregate the β-sheet-rich fibrils and metal-induced or self-aggregated Aβ aggregates, and inhibit the production of ROS. Therefore, it protected the neurons from synaptic toxicity induced by Zn²⁺– or Cu²⁺–Aβ aggregates or Aβ self-aggregation. Molecular simulations indicated that the appropriate sizes of CAM and β-sheet cavities were beneficial for the interaction between CAM and Aβ aggregates. Additionally, the hydrogen bonding preference of amino acid residues in the cavity provided a prerequisite for the interaction. Thus, CAM represents a new type of modified POM with a unique mechanism for targeting and inhibiting Aβ aggregates. The concept of this study may be applicable to other NDDs caused by protein misfolding and aggregation.

In 2019, Liu's group designed and prepared an organic platinum substituted POM, (Me₄N)₃[PW₁₁O₄₀(SiC₃H₆NH₂)₂PtCl₂] (abbreviated as Pt^IIPW₁₁) for inhibiting the aggregation of Aβ42 (Fig. 9d).³⁸ Pt^IIPW₁₁ at a dose of 8 μM exhibited a significant neuroprotective effect on neurotoxicity induced by Aβ42 aggregation, leading to an increase in cell viability from 49% to 67%. More importantly, Pt^IIPW₁₁ significantly reduced Aβ42 deposition and rescued memory loss in a mouse model of AD without obvious cytotoxicity, demonstrating its potential as a drug for AD. The ability of Pt^IIPW₁₁ to inhibit the aggregation of Aβ42 was attributed to synergistic interactions, including electrostatic attraction, hydrogen bonding, and van der Waals forces between Pt²⁺ in Pt^IIPW₁₁ and the amino group in Aβ42. Therefore, achiral ligand POMs are also an important class of modified POMs that could effectively inhibit Aβ aggregation.

3.2.3. POM-based nanocomposites. With the development of nanotechnology and materials science, the study of POMs is no longer limited to purely inorganic POMs, but also includes POM-based nanohybrid compounds, which can reduce cytotoxicity and improve the structural stability of POMs by functional combination or encapsulation of organic structures.¹⁰⁶ Metals such as platinum (Pt), cobalt (Co), tungsten (W), gold (Au), cerium (Ce) and vanadium (V) in complexes, compounds, and biological nanoparticles have been widely utilized to modify POMs.² In 2015, Gao et al. were inspired by the catalytic mechanism of serine protease to design and construct a bifunctional nanoenzyme, AuNPs@POMD-pep (AuNPs: gold nanoparticles, POMD: POM with Wells–Dawson structure, pep: peptide of N-acetyl-Cys-LPFFD).¹⁰⁷ The strong binding between AuNPs@POMD-pep and Aβ monomers, caused by electrostatic, hydrogen bonding, and hydrophobic interactions, significantly reduced the concentration of free monomers, driving the equilibrium away from aggregation. The interactions between POMD and Aβ are primarily driven by electrostatic and hydrogen bonding, while the peptide and Aβ mainly engage in hydrophobic interactions. After that, Gao et al. developed AuNPs@POMD-8pep with improved targeting ability via 8pep (octa-peptides of N-acetyl-Cys-LPFFD) on the basis of AuNPs@POMD-pep (Fig. 10a).⁸⁶In vitro experiments showed that AuNPs@POMD-8pep had serine protease and superoxide dismutase (SOD) activity, which could hydrolyze Aβ monomers and eliminate excess ROS generated within cells (Fig. 11). In 2016, Guan et al. synthesized three different types of POMs/cerium dioxide (CeONP@POMD, CeONP@POMK and CeONP@POMA) as mimetics of metalloproteinase MMP (Fig. 10b).⁸⁷ The experimental results confirmed that CeONP@POMD had the highest efficiency for hydrolyzing Aβ and reducing the overproduction of ROS that could trigger cell death.¹⁰⁸ Therefore, Ce/POM hybrid nanoparticles inhibited Aβ-induced cytotoxicity by both degrading Aβ aggregates and eliminating excess ROS.

Fig. 10 Structures of POM-based nanocomposites. (a) A bifunctional nanoenzyme, AuNPs@POMD-8pep. (b) CeONP@POMD. (c) rPOMs@MSNs@copolymers. (d) AuP nanorods. (e) Peptide@Mo-POMs. (f) AuNPs@POM@PEG.

Fig. 11 Aβ aggregation destroys the activity of NMDA receptors, leading to the generation of extracellular ROS and excess calcium influx into neurons, eventually causing mitochondrial dysfunction. ROS plays a key role in Aβ-mediated neuronal apoptosis. Dysfunctional mitochondria will further release ROS, which stimulates the production of pro-apoptotic proteins and causes apoptosis of nerve cells. AuNPs@POMD-8pep has serine protease and SOD activity, which can hydrolyze Aβ monomers and eliminate excess ROS generated within cells to treat AD.

POMs can also be used in PTT, which has received widespread attention in AD treatment due to its non-invasive nature and minimal damage to surrounding normal tissues. In 2018, Ma et al. designed and synthesized a NIR-responsive POM-based nanoplate with redox activation (rPOMs@MSNs@copolymers), which had a high photothermal effect and antioxidant activity (Fig. 10c).⁸⁸ Due to the strong NIR absorption of POMs (rPOM), rPOMs@MSNs@copolymers could convert light to local heat to decompose Aβ fibers under NIR laser irradiation. Furthermore, Aβ-induced ROS was eliminated by the antioxidant activity of rPOMs. Similarly, in 2017, Li et al. proposed a novel strategy through the self-assembly of peptide (Ac-QKLVFF-NH₂) coupled Au nanorods (AuP), which inhibited Aβ aggregates by PTT (Fig. 10d).¹⁰⁹ The AuP can effectively dissociate the amyloid protein deposits under NIR laser irradiation in mouse cerebrospinal fluid, which protects cells from Aβ-induced toxicity. These studies may provide new insights for developing POM-based AD therapy in combination with PTT.

In 2019, peptide modified Mo POM nanoparticles (Mo-POMs) were synthesized by the self-assembly of Aβ targeting peptide (Ac-QKLVFF-NH2) and Mo-POMs (Fig. 10e).⁹¹ Importantly, by modification with the Aβ targeting peptide, the Mo-POM nanoparticles exhibited enhanced BBB penetration and a high binding affinity with Aβ species. Directed interactions between the peptide@Mo-POM nanoparticles and Aβ resulted in the suppression of Aβ aggregation and disaggregation of Aβ fibrils by stabilizing the native structure of Aβ monomers. Furthermore, in vitro experiments revealed that peptide@Mo-POMs could target and be well absorbed by PC12 cells to inhibit intracellular Aβ aggregation and reduce the Aβ aggregate-induced cytotoxicity.

Recently, a tri-component nanohybrid system, AuNPs@POM@PEG, was produced based on gold nanoparticles (AuNPs) covered with POMs (Fig. 10f).¹⁷ The presence of PEG increased the stability of the nanosystem, which could be preserved for 14 weeks, demonstrating good long-term stability in physiological media. AuNPs@POM@PEG could effectively inhibit Aβ aggregation via a synergetic effect between AuNPs and POM components that allowed inhibition levels of up to 75%. AuNPs@POM@PEG could cross the BBB at similar levels to other nanovehicles reported for drug delivery into the brain. These results suggest that AuNPs@POM@PEG or other POM-functionalized AuNPs could serve as promising candidates for the treatment of AD, which could be further extended to other NDDs.

In summary, protein aggregation plays a crucial role in the pathogenesis of AD. Among the six classic POMs, the Wells–Dawson structured POM shows the best inhibitory effect on Aβ protein aggregation. Organic or inorganic hybridization of POMs, such as transition metal and rare Earth metal substitution, and organic ligand modification, can effectively improve the inhibitory effect on protein aggregation. In addition, the combination of POMs and nanomaterials can improve the inhibitory effect on protein aggregation. The complex system may prompt the design of new multifunctional materials (tracking, drug loading, targeted drug release, etc.) for AD treatment. We speculate that the size, surface charge and ligands of POMs may play important roles in the recognition and inhibition of Aβ aggregation. Further work is needed to elucidate the exact inhibitory mechanisms through which these POMs act. In addition, the challenge lies in reducing potential cytotoxicity and improving stability before POMs can be applied in clinical treatment.

4. Application of POMs in AD via targeting S100A9

The pro-inflammatory S100A9 protein is recognized as an important contributor to neuroinflammation associated with the pathogenesis of AD. Studies have shown that the expression of S100A9 is upregulated in neuritic plaques and glial cells. Upregulated S100A9 can activate the p38 mitogen-activated protein kinase cascade, NF-kB or calcium-dependent signal transduction and stimulate the production of proinflammatory cytokines, leading to inflammation.¹¹⁰ Unlike other pro-inflammatory factors, S100A9 has the unique ability to spontaneously self-assemble amyloids under physiological conditions. During inflammation, S100A9 levels continue to rise, further leading to amyloid formation and aggregates.¹¹¹ Therefore, S100A9 contributes to the development of AD via driving a self-reinforcing cycle that sustains inflammation and amyloid aggregation. In 2021, Chaudhary et al. demonstrated that two selected nanosized niobium POMs (Nb₁₀ and TiNb₉) served as effective inhibitors of S100A9 amyloid protein assembly (Fig. 12).⁴¹ Molecular dynamics simulations revealed that both Nb10 and TiNb9 bound to the S100A9 homo-dimer by forming ionic interactions with the positively charged Lys residue-rich patches on the protein surface. The region encompassing Lys50 to Lys54, characterized by high amyloid propensity, was the key sequence involved in S100A9 amyloid self-assembly. As the concentration of POMs increased, the long fibrillar structure of S100A9 completely disappeared, while short elongated stretches were formed.⁴¹ Thus, an alternative strategy for POM-based AD therapy is to inhibit the aggregation of S100A9 and ameliorate the self-reinforcing cycle of inflammation and amyloid aggregation.

Fig. 12 Structures of (a) decaniobate Nb₁₀ = [Nb₁₀O₂₈]⁶⁻ and (b) monotitanoniobate TiNb₉ = [TiNb₉O₂₈]⁷⁻. NbO₆ polyhedra: blue, TiO₆ polyhedra: light green, and oxygen atoms: red balls.

5. Application of POMs in prion disease

As mentioned before, conformational conversion of soluble PrP^c into insoluble PrP^Sc is a central aspect of prion disease. Therapeutic strategies to treat prion disease have been focused on the recognition of PrP^Sc aggregates for inhibition or clearance. Initially, Lee et al. developed a conformation-dependent immunoassay (CDI) for the detection of the infectious isoform of PrP^Sc.¹¹² Na₄[SiW₁₂O₄₀], K₅[BW₁₂O₄₀] and Na₆[H₂W₁₂O₄₀] contained anions with the same Keggin structure as that of [PW₁₂O₄₀]³⁻, while central P^IV atom substitution resulted in an increasing negative charge along the [SiW₁₂O₄₀]⁴⁻, [BW₁₂O₄₀]⁵⁻ and [H₂W₁₂O₄₀]⁶⁻ series. They were able to selectively precipitate PrP^Sc from tissue homogenates by surface charge, facilitating the detection of prion infection. In addition, Keggin POMs, which carry a negative charge and exhibit conformational selectivity, could generate electrostatic interactions between multiple PrP^Sc oligomers. Their binding sites were located in the clefts of one or more positively charged residues on PrP^Sc. At the same time, the size, surface property and charge density of the POMs have an impact on the binding affinity with PrP^Sc.¹¹³ For example, the large sized POM inhibits the precipitation of PrP^Sc. POMs can be used not only for the detection of prions, but also for the inhibition of prion aggregation. The phosphotungstate anion (PTA), one of the Keggin type POMs, is widely used to detect and inhibit PrP^Sc aggregation. PTA can selectively bind to PrP^Scvia electrostatic interactions.⁹⁵ Other studies have shown that PrP^Sc from the brain of patients binds to apolipoprotein B (apoB) in very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), which enhances the participation of lipoproteins in PrP^Sc aggregation.¹¹⁴ However, the affinity between PTA and PrP^Sc is stronger than the affinity between PrP^Sc and apoB. Thus, PTA can separate PrP^Sc from lipoproteins by strongly binding to PrP^Sc, preventing lipoproteins from participating and PrP^Sc from aggregating.

Due to the excellent redox properties, POMs also have the ability to oxidize PrP^Sc, which has a potential inhibitory effect on the aggregation of amyloid peptides. Recently, Li et al. developed vanadium-substituted Keggin POMs.⁹⁷ The oxidation of PrP^Sc by POMs depended not only on the electron acceptance capacity of POMs, but also on their stability. Vanadium substitution affected the band structure of POMs and conferred improved stability on them. At the same time, the substitution of W/Mo by vanadium disrupted the symmetrical electron distribution of POMs, resulting in an enhanced local electron distribution on the bridging O atom, which strengthened the hydrogen bond to the histidine site of PrP^Sc (Fig. 13). Therefore, vanadium-substituted POMs showed a good inhibitory effect on PrP^Sc aggregation and resulting neurotoxicity by oxidation.

Fig. 13 Interaction modes between V-substituted W/Mo-POMs and PrP.

6. Application of POMs in PD

As a chronic NDD, PD is difficult to diagnose due to the site of pathology and clinical phenotype.¹¹⁵ Therefore, the development of real-time quantitative methods for PD biomarkers is essential for clinical diagnosis.¹¹⁶ In 2023, Shetty et al. designed and constructed a polyoxometalate–γ-cyclodextrin metal–organic framework (POM-γCD MOF), which could be used as an excellent electrocatalyst to develop highly selective sensors for detecting the in situ release of dopamine that served as a major biomarker of PD.¹¹⁷ POM-γCD MOF generated multiple modes of signals such as electrochemical and colorimetric signals, which could be converted into digital signals by a smartphone read-out platform.

In addition to AD and prion disease, the application of POMs in the treatment of other NDDs has also begun. Recently, Kalita et al. found that hen egg white lysozyme (Lyz) could be converted into amyloid fibrils; this was considered to be an excellent model protein for the study of NDD-associated protein aggregation.¹¹⁸ Utilizing this model, they showed that Keggin POMs such as phosphomolybdic acid and silicomolybdic acid, inhibited the aggregation of Lyz via hydrogen bonding and electrostatic interactions. It also indicates the possibility of suppressing NDD-associated protein aggregates by Keggin POMs. In addition, MOCs are widely recognized as novel nanoagents, which have broad application prospects in nanomedicine due to their ultrafine size, low toxicity and high renal clearance.¹¹⁹ In our recent study, we rationally introduced chirality into titanium oxide nanoclusters by chiral ligand exchange to synthesize R-Ti₁₀Cd₆ and S-Ti₁₀Cd₆ (R = R-hydrobenzoin, S = S-hydrobenzoin).¹²⁰ Furthermore, we found that R-Ti₁₀Cd₆ but not S-Ti₁₀Cd₆ could effectively recover the loss of dopaminergic neurons and defects in dopamine-dependent locomotion behaviors in a C. elegans model of PD. As an important class of MOCs, POMs may have similar bioactivity that might be employed to explore their therapeutic application in PD.¹²¹ Indeed, we have screened a series of POMs in a C. elegans model of PD and identified two types of POMs that were able to inhibit α-synuclein aggregation and recover the defects in locomotion behaviors (Chen et al., unpublished data). Therefore, the application of POMs and their derivatives could be extended to the treatment of PD in the future.

7. Application of POMs in ALS

LLPS of biomolecules has been used to explain the formation of membraneless condensates such as stress granules and protein aggregates, and serves as a mechanism underlying the pathogenesis of NDDs that are closely associated with the transformation of soluble proteins into insoluble aggregates and amyloid fibrils.^122,123 As mentioned before, mutated FUS and TDP-43 mislocalize in the cytoplasm and form protein aggregates via LLPS, leading to the development of ALS.¹²⁴ Most recently, Zhang et al. demonstrated that graphene quantum dots (GQDs) could not only inhibit FUS LLPS but also disassemble FUS droplets in vitro through electrostatic and hydrophobic interactions.¹²⁵ Similarly, halogen-doped GQDs inhibited abnormal LLPS of TDP-43 and reduced TDP-43 aggregates.¹²⁶ As a type of MOC with a negative charge and large surface, POMs exist in the form of completely hydrophilic surfaces, with a uniform shape and intact molecular structures in dilute solutions.¹²⁷ POMs can broadly attract positive charges, which confer on them the ability to selectively attract high-valence or monovalent ions with smaller hydrated sizes. POMs actually possess the ability to modulate LLPS of solutions through electrostatic, hydrophobic and counterion-mediated attractions.¹²⁸ Therefore, POMs may also have potential in ALS treatment via suppressing the abnormal LLPS of FUS and TDP-43 proteins.

8. Conclusion and outlook

NDDs are characterized by the progressive loss of neurons associated with protein deposits and show changes to the physicochemical properties of the brain and peripheral organs. The most common protein aggregates involved in the pathogenesis of NDDs are Aβ and S100A9 in AD, prion protein in prion disease, α-synuclein in PD, and TDP-43 and FUS in ALS.^129,130 Among these, the deposition and accumulation of Aβ lead to the formation of amyloid plaques, which are one of the basic features of AD patients, leading to neuronal toxicity in the brain.¹³¹ In the normal brain, there is a balance between Aβ production and clearance. However, with aging, mutations in genes associated with Aβ aggregation lead to a series of problems such as a decrease in the number of degradative enzymes, a decrease in the number of receptors that mediate the clearance or reduction of Aβ and others that cause protein misfolding and aggregation with uncontrolled chronic neuroinflammation.¹³² However, the increase in Aβ aggregation leads to synapsis loss and dysfunction, mitochondrial damage, oxidative stress, and the dysregulation of homeostasis.¹³³ Therefore, inhibiting the formation of protein aggregates or removing the formed aggregates represents a promising therapeutic strategy for NDDs.

An increasing number of studies have demonstrated that POMs possess the ability to selectively recognize and inhibit protein aggregation, which means POMs have potential for application in NDD treatment. The mechanisms underlying the therapeutic effect of POMs can be summarized as follows. Firstly, as an inorganic nanomaterial with a large negative charge, POMs can cross the BBB to target Aβ. Through electrostatic interactions and histidine chelation, POMs and POMds strongly bind to Aβ monomers carrying positively charged cationic HHQK clusters and inhibit the formation of Aβ aggregates. Similarly, POMs can bind to the region with concentrated positive charge on the surface of S100A9 protein and inhibit the formation of S100A9 aggregates. Secondly, protein aggregates are usually chiral molecules, such as Aβ. Modified POMs with a corresponding chiral conformation can potently improve the interaction between POMs and protein aggregates by enantioselectivity, leading to the enhanced recognition of protein aggregates. Thirdly, POMs can be used as a photocatalyst to generate free radicals, which destroy the secondary structure of Aβ aggregates and depolymerize them. Fourthly, POMs act as NIR photothermal agents to convert light into local heat, leading to the decomposition of Aβ aggregates. Finally, through the antioxidant properties of POMs, excess ROS produced by Aβ aggregates can be eliminated to avoid initiating cell death. Overall, POMs have a significant effect on inhibiting or clearing protein aggregates due to their diverse functions.

However, challenges also remain with the rational and optimal design and application of POMs in NDDs. Firstly, a spatial structure relationship between protein monomers (e.g. Aβ40 and Aβ42 monomer) or normal isoforms (e.g. PrP^c) and POMs versus the relationship between protein aggregates and POMs should be further investigated to ensure POMs selectively and preferentially target protein aggregates rather than monomer or normal isoforms so that their normal physiological function will not be disturbed. Secondly, the introduction of other ligands or properties (e.g. chirality, targeting peptide, antioxidant and hydrolyzing activity) to rationally modify POMs is necessary to improve the enantioselectivity or inhibitory effect towards protein aggregates. Additional instant structure and interaction analysis of POMs with pathogenic proteins will be helpful for understanding their biological mechanisms and theories, which will greatly promote the design of functional POM materials for targeting protein aggregation. Thirdly, the therapeutic effect of POMs is important, but the potential toxicity of POMs should also be carefully evaluated. Both of them could include studies at multiple levels, including cell and animal models that are closer to clinical trials. Finally, protein aggregates are a common hallmark and pathogenic factor of NDDs. While current studies of POMs are limited to protein aggregates associated with AD and prion disease only, future studies could modify the specificity of POMs and extend it to target α-synuclein, TDP-43 and FUS aggregates for therapeutic applications in PD and ALS. Addressing these issues will advance the applications of POMs to target NDDs in the future.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the support of this work by the National Natural Science Foundation of China (NSFC 31970755 and 21801226), the Natural Science Foundation of Zhejiang Province (LY21C120001 and LY20B010002) and the Zhejiang Normal University Fund.

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Footnote

† These authors contributed equally to this work.

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