SERS-Based Optical Nanobiosensors for the Detection of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.

Keywords: Alzheimer’s disease; SERS; biosensor; disease diagnosis; fluid biomarkers; nanoparticles.

Figure 1

The main pathologies of Alzheimer’s disease ( AD). Risk factors associated with late-onset Alzheimer’s disease (LOAD) are thought to contribute to at least one of six main pathological processes: oxidative stress and oxysterol production, phosphatidylserine-exposed neurons, pro-inflammatory cytokines, amyloid-beta aggregation and vascular pathology, tau pathology, and glial cell reactivity.

Figure 2

Distribution of AD biomarkers. AD biomarkers can be present intracellular in nerve cells. Additionally, these biomarkers can be present in the bloodstream through various mechanisms, including cellular cytosis, protein channels, and direct osmosis. Furthermore, AD biomarkers can pass through tight junctions and enter the CSF. BBB means blood–brain barrier; CFS means cerebrospinal fluid.

Figure 3

Types of light scattering. (A) All three different ways in which light can be re-emitted: Rayleigh scatter, Stokes Raman scatter, anti-Stokes Raman scatter. (B) Energy level change for different scattering: the energy level of Rayleigh scatter remains unchanged; the energy level of Stokes Raman scatter decreases; the energy level of anti-Stokes Raman scatter increases.

Figure 4

Types of surface-enhanced Raman scattering (SERS) enhancements. (A) Electromagnetic enhancement principle of SERS: metal conductive electrons are excited into collective oscillations generating an electromagnetic field highly localized in the metal–dielectric interface when irradiated with light. (B) Chemical enhancement principle of SERS: the interaction between nanoparticles and molecules can lead to mutual excitation of the Raman polarizability (indicated by a thin purple arrow) from the local electromagnetic field (indicated by a green arrow), resulting in the generation of enhanced Raman signals from the molecule.

Figure 5

Types of SERS substrates. (A) Various nanocolloid substrates, which are constructed by using nanoparticles, nanorods, nanoflowers, alloy nanoparticles, core-shell nanoparticles, and so on. (B) Various solid substrates, which are constructed by using nanoparticles, nanorods, nanoflowers, alloy nanoparticles, core-shell nanoparticles, and so on.

Figure 6

Schematic illustration of the principle of the label-free assay strategy. The fingerprint information for a target can be obtained by detecting SERS spectroscopy, where target molecules are directly attached to the surface of metal nanoparticles without any labels under higher scattering efficiencies.

Figure 7

Schematic illustration of a 3D SERS substrate via solvent-assisted nanotransfer printing. (a) Schematic of the S-nTP process to form a 3D SERS substrate.i means the master mold pattern; ii means PMMA replication via spin-coating method; iii and iv mean gold nanowires were formed through angle deposition of gold via e-beam evaporation on the PMMA replicas; v means the adhesion between the PMMA and the PI film; vi means a single layer of gold nanowires was successfully transfer-printed on the substrate by gentle pressing with a PDMS pad; vii means 3D SERS substrate is successfully constructed. (b) SEM images of the 3D SERS substrate consisting of stacked gold nanowire array sheets. A region where the first and the second sheet overlaps (left). SEM images of the 3D SERS structure stacked with two sheets (middle) and four sheets (right). (c) Illustration of the 3D SERS substrate illuminated with a Raman excitation laser and strong local E-fields formed around nanowires according to the excitation laser polarization. The figure adapted from ref. [109] Copyright © 2020 American Chemical Society.

Figure 8

Schematic illustration of the tag synthesis process. First, the plasmonic core is modified with Raman reporters and then coated with a protective layer such as bovine serum proteins, which are used for enclosing nonspecific binding sites. Finally, targeting ligands, such as antibodies and aptamers, are attached to the surface of the plasmonic core to form SERS tags.

Figure 9

Schematic illustration of the fabrication of AuNP-conjugated SiNR arrays. Close-packed monolayer of PS nanospheres on a clean Si-reduced diameter of PS by reactive ion etching, Au deposition, metal-assisted chemical etching, removal of Au/PS, conjugation with Au nanoparticles. The figure is adapted from ref. [118] Copyright © 2017 American Chemical Society.

Figure 10

Mechanism of the magnetic separation-SERS based detection. First, magnetic nanoparticles are added into the sample to capture target molecules. and then, the captured complexes are separated and enriched using a magnetic device. Finally, the separated complexes are detected by the SERS detection device. MB means magnetic bead.

Figure 11

Schematic illustration of multiplied microfluidic platforms. The multiplied microfluidic platforms consist of lateral flow immunoassay devices, microfluidic chips, droplet-based devices, paper-based devices, and so on, which have the advantages of small size and simple operation and can rapidly and accurately diagnose AD by analyzing the blood and CFS from the patients.