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WIREs Nanomed Nanobiotechnol
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Functional nanoassemblies for the diagnosis and therapy of Alzheimer's diseases

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Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects populations around the world. Many therapeutics have been investigated for AD diagnosis and/or therapy, but the efficacy is largely limited by the poor bioavailability of drugs and by the presence of the blood–brain barrier. Recently, the development of nanomedicines enables efficient drug delivery to the brain, but the complex pathological mechanism of AD prevents them from successful treatment. As a type of advanced nanomedicine, multifunctional nanoassemblies self‐assembled from nanoscale imaging or therapeutic agents can simultaneously target multiple pathological factors, showing great potential in the diagnosis and therapy of AD. To help readers better understand this emerging field, in this review, we first introduce the pathological mechanisms and the potential drug candidates of AD, as well as the design strategies of nanoassemblies for improving AD targeting efficiency. Moreover, the progress of dynamic nanoassemblies that can diagnose and/or treat AD in response to the endogenous or exogenous stimuli will be described. Finally, we conclude with our perspectives on the future development in this field. The objective of this review is to outline the latest progress of using nanoassemblies to overcome the complex pathological environment of AD for improved diagnosis and therapy, in hopes of accelerating the future development of intelligent AD nanomedicines. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging
Pathogenetic pathways of the occurrence of AD. Aβ peptides are cleaved from APP by enzymes (e.g., BACE1; step1) and released into the extracellular milieu. The failure of astrocytes to clear Aβ via low‐density lipoprotein receptor‐related protein 1 (LRP1) and the presence of metal ions result in the aggregation of Aβ (step 2). As a confrontation, Aβ plaques are degraded by the endoproteases released by astrocytes and phagocytosed by microglia (step 3). The conformational Aβo disassociated from Aβ plaques attach to the synapses of neurons (step 4), and participate in the aggregation/hyperphosphorylation of tau by working together with GSK‐3β and APOE4 (step 5). The DAM formed by Aβ overactivated microglia not only produces ROS, causes neuroinflammation and the overpruning of synapses, but also contributes to the spreading of tau tangles among neurons (step 6). Besides, the Aβ aggregates formed within cells causes the dysfunction of mitochondria and thereby further contributing to the production of ROS (step 7)
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Nanoassemblies for the tau‐targeted treatment of AD. (a and b) Schematic illustration of the designed synthetic procedure of CeNCs/IONC/MSN‐T807‐MB and its tau‐targeted synergistic treatment. (c) Schematic illustration of the preparation of HMPWCs and (d and e) the effect of HMPWCs on the tau‐related AD‐like neuropathologySource: (a and b) Reprinted with permission from Chen et al. (2018). Copyright 2018 American Chemical Society; (c and d) reprinted with permission from L. Cai, Yang, et al. (2020). Copyright 2020 Elsevier
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Nanoassemblies for the Aβ‐targeted treatment of AD. (a) Schematic illustration of the Aβ nanodepletors' anti‐amyloidogenic capabilities; (b and c) brain sections images of Aβ plaques stained by (b) Thioflavin S and (c) anti‐Aβ antibody followed by secondary antibody containing Alexa Fluor 568; (d and e) imaging analyses of Aβ plaques using (d) ThS stained images and (e) immunostained images; (f) ELISA measurements of relative Aβ42 levels of BSA‐decorated nanostructure injected brains and Aβ nanodepletor injected brains; (g) schematic illustration of MCNA synthesis; (h) schematic illustration of Aβ capture and magnetic separation by MCNAs. (i) MCNA concentration‐dependent Aβ peptide capture efficiency; (j) plasma Aβ concentrations measured before and after the Aβ cleansing treatment with MCNAs (1.8 × 10−3 m [Fe]); (k) ROS levels in the plasma samples nontreated (transgenic, Tg) or treated with different types of NPsSource: (a–f) Reprinted with permission from Jung et al. (2020) Copyright 2020 Wiley; (g–k) reprinted with permission from D. Kim et al., 2019 Copyright 2019 Wiley
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Nanoassemblies for Aβo detection. (a) The schematic illustration of the dual‐modal imaging nanoassembly [email protected]2@F‐SLOH upon binding with Aβ; (b) transmission electron microscope (TEM) images of [email protected]2@F‐SLOH; (c) NIR fluorescence images and ex vivo fluorescence staining of the brain slices acquired from the WT mouse and transgenic (Tg) mice of different ages (7, 9, and 11 months) after injection of [email protected]2@ F‐SLOH (40 mg kg−1) for 6 h; (d) in vivo MRI images and the respective pseudocolor mapped images of the brains of WT and Tg mice at different ages before injection of [email protected]2@F‐SLOH (row 1–2) and 6 h post injection of 40 mg kg−1 [email protected]2@F‐SLOH via tail vein (row 3–5). (e) Schematic illustration of Aβo sensitive assay and imaging based on target‐triggered DNAzyme‐driven 3D DNA walker fluorescence signal amplification technology; (f) confocal fluorescence images of BV‐2 cells incubated with 3D DNA walker nanoassembly, 3D DNA walker nanoassembly/Zn2+, 3D DNA walker nanoassembly/Aβo, and 3D DNA walker nanoassembly/Zn2+/Aβo. (g) in vivo fluorescence images and (h) relative fluorescence signal [F(t)/F(pre)] of the WT (top row) and Tg (bottom row) mice at selected time points before or after injection; (i) relative fluorescence signal [F(t)/F(pre)] of WT and Tg mice at 240 min after injection; (j) H&E staining of major organs of mice with/without 3D DNA walker nanoassembly injectionSource: (a–d) Reprinted with permission from C. Wang et al. (2020). Copyright 2020 Wiley; (c–d) reprinted with permission from Yin et al. (2020). Copyright 2020 ACS
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The delivery routes of nanomedicines to the brain. (a) The commonly used administration routes for delivering nanomedicines to brain; (b) BBB transport pathways for nanomedicines administrated by IV‐route; (c) olfactory and trigeminal pathways for nanomedicines administrated by IN‐route; (d) lymphatic vasculature pathway for nanomedicines administrated by SC‐route
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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