Research has shown that AβOs possess a remarkable ability to penetrate cell membranes, largely due to their capacity to form porins within the lipid bilayer. This ability arises from the increased presence of β-sheet structures in AβOs, which can create distinct rafts in the membrane. These ring-shaped oligomers adhere to the cell membrane and inflict damage either by directly penetrating the membrane or by aggregating into fibrils that disrupt cellular integrity. Once internalized, AβOs activate N-methyl-ᴅ-aspartate-type glutamate receptors (NMDARs) located on neuronal membranes. This activation triggers endoplasmic reticulum (ER) stress through the stimulation of phospholipase C, leading to an influx of calcium ions (Ca2+) into the cytosol . Elevated Ca2+ levels result in the accumulation of reactive oxygen species (ROS) and reactive nitrogen species, contributing to oxidative stress within the cell . The increase in cytosolic Ca2+ also promotes the phosphorylation of ATP proteins, which, in turn, leads to the enhanced production of Aβ42 and AβOs, creating a vicious cycle. This cascade ultimately results in further spikes in intracellular Ca2+ concentrations sourced from the ER, which is linked to memory impairments commonly associated with AD. Additionally, elevated cytosolic Ca2+ activates the enzyme calcineurin, which is implicated in the activation of the Bcl-2-associated death promoter (BAD). This process, coupled with oxidative stress pathways originating from mitochondrial dysfunction, facilitates the release of cytochrome c from the mitochondria. This release is a key event that promotes caspase activation, initiating pro-apoptotic signaling that drives neuronal apoptosis . Furthermore, AβOs can disrupt the membranes of endosomes and lysosomes, exacerbating neuronal cell death .

AβOs are small aggregates formed from the misfolding and aggregation of amyloid-β (Aβ) peptides, primarily Aβ40 and Aβ42. These oligomers typically consist of a limited number of Aβ monomers, often ranging from trimers to tetramers, but they can form larger aggregates under certain conditions. Their small size and unique structural properties contribute to several challenges in therapeutic targeting. They are considerably smaller than fibrillar aggregates and plaques, making them difficult to target with conventional binding agents. AβOs exhibit significant heterogeneity in size and conformation. This variability means that a single therapeutic agent may not effectively recognize all oligomeric forms, complicating the development of broad-spectrum therapies. Unlike larger aggregates, which may present multiple binding sites, AβOs have fewer defined surface characteristics that can be targeted. AβOs can interconvert between different oligomeric states and may also exist in equilibrium with monomeric and fibrillar forms. This dynamic nature poses a challenge for therapies that rely on specific binding, as the target may change rapidly in response to environmental factors or therapeutic intervention. As a result, the predominant strategies for targeting AβOs have largely been confined to biologics, particularly monoclonal and polyclonal antibodies. The advantages of using antibodies stem from their remarkable capacity to recognize conformational epitopes that are unique to various oligomeric forms, thereby facilitating the selective targeting of pathogenic AβOs.

The most widely utilized monoclonal antibodies in AD research are 6E10 and 4G8 . These antibodies were generated by immunizing mice with specific peptide fragments of Aβ, allowing them to bind effectively to amyloid aggregates. Importantly, the development of “conformation-dependent” antibodies, such as A11 and OC, marked a significant advancement in the field, as they were among the first to differentiate between AβOs and AβFs. This distinction is crucial for understanding the pathophysiology of AD, as oligomers are believed to be more toxic than fibrils .

Table 1: Classification of therapeutic strategies targeting AβOs and their mechanisms of action.

Recent advancements have positioned immunotherapeutic approaches utilizing anti-Aβ antibodies as some of the most promising strategies for the treatment of AD. Notably, the first generation of anti-Aβ antibody therapies, including aducanumab, lecanemab, and donanemab, has demonstrated significant therapeutic potential in combating AD. Aducanumab and lecanemab have already received FDA approval, while donanemab is currently undergoing clinical evaluation . In a noteworthy study by Sandberg et al., an oligomer-specific antibody known as ALZ 201 was reported to effectively mitigate the toxic effects associated with extracts from AD brains. This research confirmed that ALZ 201 selectively recognizes AβOs and, interestingly, demonstrated efficacy in protecting neurons exposed to AD brain extract. ALZ 201 is presently in preclinical development, highlighting its potential as a therapeutic candidate . Lecanemab, another anti-Aβ antibody, has been found to exhibit a higher affinity for Aβ protofibrils characterized as “beaded” curvilinear fibrils and recognized as a specific form of AβOs than other known antibodies such as aducanumab or gantenerumab. Furthermore, clinical observations have indicated that treatment with lecanemab is associated with a reduction in cognitive decline, underscoring its promise as a viable therapeutic option in the fight against AD .

Although conventional approaches for diagnosing and targeting AβOs have laid the foundation for AD treatment, they often face limitations. For example, monoclonal antibodies, while capable of binding AβOs, may also interact with other forms of Aβ, including fibrils or monomers, leading to off-target effects and reduced efficacy. Recent advancements in nanotechnology offer a promising alternative with NPs specifically designed for AD diagnosis and AβO inhibition. These NPs possess unique properties, including variable size and shape and readily modifiable surfaces. These features allow for targeted and effective therapeutic strategies. In this section, we discuss NPs specifically designed for the diagnosis and inhibition of AβOs.

Table 2: NP-based strategies for diagnosing and inhibiting AβO formation, as well as mitigating the associated toxicity.

In this review, we systematically categorize NPs used for the diagnosis and inhibition of AβOs based on their composition and functionalization. This bifurcation allows for a clearer understanding of the diverse mechanisms and applications of NPs in addressing AD. We have organized the NPs into four primary categories, namely, carbon based nanomaterials (CNMs), metal based NMs, biomimetic NMs and antibody-functionalized NMs.

Recent advances in nanomedicine have spotlighted CNMs because of their remarkable physicochemical properties, diverse structural forms, and potential applications in combating NDs. The unique characteristics of CNMs, including their hydrophobic surfaces and variable dimensions, enable them to interact effectively with biomolecules, making them valuable tools in biomedical research and therapeutic applications. CNMs can be categorized into three primary forms, namely, zero-dimensional fullerenes (e.g., C60), one-dimensional carbon nanotubes (CNTs), and two-dimensional graphene. Each of these NMs possesses distinct attributes that facilitate their engagement with proteins and peptides, particularly those associated with NDs like AD. Research has demonstrated the ability of fullerenes to prevent the aggregation of Aβ peptides. For instance, molecular dynamics simulations have shown that fullerenes inhibit the fibrillation of the hydrophobic KLVFFAE peptide by disrupting the formation of β-sheet oligomers. This property is particularly significant as β-sheet formation is a critical step in the aggregation pathway leading to neurotoxic amyloid fibrils . Further investigations revealed that fullerene C60 interacts strongly with non-polar aliphatic groups in polar residues of the GNNQQNY peptide, effectively redirecting the formation of potentially toxic oligomers towards disordered coil structures. This mechanism not only hinders fibril formation but also shifts the balance toward less harmful aggregates . Single-walled carbon nanotubes (SWCNTs) have emerged as another promising CNM for the detection and inhibition of AβOs. Studies indicate that hydroxylated SWCNTs significantly inhibit the β-sheet formation of Aβ peptides . By facilitating the formation of disordered aggregates, these nanomaterials diminish the aggregation propensity of Aβ peptides, thereby mitigating their neurotoxic effects . In addition to their inhibitory capabilities, SWCNTs can serve as effective sensors for AβOs. Their ability to interfere with β-sheet formation, a hallmark of Aβ aggregation, has been confirmed through comprehensive molecular dynamics simulations. These studies reveal that SWCNTs interact with the hydrophobic residues of Aβ peptides, particularly through π-stacking interactions with aromatic amino acids such as phenylalanine. This interaction destabilizes the prefibrillar β-sheet structures, preventing the formation of toxic oligomers and promoting the aggregation of less harmful conformations . Moreover, the development of positively charged carbon quantum dots has shown promise in preventing the aggregation of amyloid proteins, specifically by inhibiting the formation of hetero-oligomers between islet amyloid polypeptide (IAPP) and Aβ42. Such findings highlight the versatility of CNMs in addressing different aspects of amyloid aggregation . In summary, CNMs present a multifaceted approach to the detection and inhibition of AβOs. Their unique structural properties and interactions with amyloid peptides hold significant potential for the development of innovative therapeutic strategies aimed at combating NDs. As research in this field continues to advance, the integration of CNMs into clinical applications may offer new avenues for early detection and intervention in AD and related disorders.

Metal NPs have emerged as pivotal tools in the detection and inhibition of Aβ1–42 oligomers. Their unique optical and electrical properties, particularly those of gold and silver NPs, enhance sensitivity and specificity in identifying the early stages of Aβ aggregation. By binding to AβOs, these NPs facilitate label-free detection methods such as SPR, colorimetric changes, and fluorescence amplification, enabling straightforward real-time monitoring of oligomer formation. This innovative approach not only deepens our understanding of amyloid pathology but also contributes to the development of diagnostic strategies for NDs. Zhou and colleagues introduced an advanced electrochemical aptasensor that utilizes metal-organic frameworks (MOFs) as signal probes for detecting AβOs. They engineered an electrode modified with gold nanoflowers to capture targets, employing aptamer-tagged gold nanoparticle/Cu-MOFs conjugates to produce sensitive signals. This resulted in a highly effective sandwich sensor capable of detecting AβOs in a linear range from 1 nM to 2 μM, demonstrating a correlation coefficient of 0.996 and a low detection limit of 0.45 nM . Phan and team developed a robust and straightforward method for creating multichamber paper devices using wax printing techniques, which they applied to detect AβOs. This approach leverages copper-enhanced gold nanoprobe colorimetric immunoblotting, achieving detection limits as low as 23.7 pg/mL, visible through a smartphone camera, and up to 320 pg/mL with the naked eye . Zhao and collaborators utilized AuNPs embedded in various matrices to construct three-dimensional layers for detecting AβOs. Among their innovations, PrPC/AuNPs embedded in a Ppy-3-COOH matrix (AuNPs-E-Ppy-3-COOH) exhibited superior sensitivity, with a detection range spanning from 10−9 to 103 nM . An electrochemical, label-free aptassay developed by Gallo-Orive et al. incorporates graphene oxide–gold nanoparticles/nickel/platinum nanoparticles for the rapid and accurate detection of AβOs in complex clinical samples, such as brain tissue and CSF from Alzheimer’s patients. This method showcased exceptional sensitivity with a limit of detection of 0.10 pg/mL, demonstrating reproducibility and rapidity .