Cu²⁺‐Chelatable and ROS‐Scavenging MXenzyme as NIR‐II‐Triggered Blood–Brain Barrier‐Crossing Nanocatalyst against Alzheimer's Disease

Abstract

Transition‐metal dyshomeostasis has been identified as a critical pathogenic factor for the aggregates of amyloid‐beta (Aβ) peptide, which is associated with the onset and progression of Alzheimer's disease (AD). Excessive transition‐metal ions, especially copper ion (Cu2+), catalyze the formation of reactive oxygen species (ROS), triggering neuroinflammation and neuronal cell apoptosis. Therefore, developing a robust chelating agent can not only efficiently bind toxic Cu2+, but also simultaneously scavenge the over‐generated ROS that is urgently needed for AD treatment. In this work, a 2D niobium carbide (Nb2C) MXene‐based nano‐chelator is constructed and its performance in suppressing Cu2+‐induced accumulation of aggregated Aβ peptide and acting as a nanozyme (MXenzyme) with powerful antioxidant property to scavenge excess cellular ROS is explored, and the intrinsic mechanism is revealed by computational simulation. Importantly, the benign photothermal effect of Nb2C MXenzyme demonstrates the facilitated permeability of the blood–brain barrier under near‐infrared laser irradiation, conquering limitations of the most conventional anti‐AD therapeutic agents. This work not only demonstrates a favorable strategy for combating AD by engineering Nb2C MXenzyme‐based neuroprotective nano‐chelator, but also paves a distinct insight for extending the biomedical applications of MXenes in treating transition‐metal dyshomeostasis‐and ROS‐mediated central nervous system diseases.

Advanced nanomaterials for modulating Alzheimer's related amyloid aggregation

“…Adsorption/size effect Delay [85] GO-ThS Photothermal Disaggregation [91] GOIO Adsorption Inhibition [84] GO@Dau Adsorption/anti-oxidation Inhibition/ Disaggregation [94] g-C 3 N 4 Chelation Inhibition/Disaggregation [108] g-C 3 N 4 @Pt Noncovalent interactions/ platinum coordination/ photooxygenation Inhibition/Disaggregation [105] Au/g-C 3 N 4 Photooxygenation Disaggregation [104] GO/g-C 3 N 4 Photooxygenation Disaggregation [106] g-C 3 N 4 Photooxygenation Inhibition [107] BP Adsorption Regulate the aggregation [118] PEG-LK7@BP Electrostatic/ hydrophobic interactions Inhibition [119] BP@BTA Photooxygenation Inhibition [126] MoS 2 Adsorption Modulation [137] MoS 2 -Co Photothermal Inhibition/Disaggregation [141] MoS 2 /AuNR Photothermal Modulation/Disaggregation [140] AuNPs [120] BNNS Adsorption Modulation [144] 3 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 field of biomedicine in recent years. [149] The edge effect, quantum confinement effect, ultrasmall size and good biocompatibility of 0D nanomaterials endow their many functions and special performance, such as photoluminescence (PL), tissue penetration, bioactivity, and drug loading capability.…”

“…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.…”

“…2D COFs, MXenes, hexagonal boron nitride and so on have also been reported for use in AD diagnosis and treatment. 120,143,144…”

“…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.…”

“…MXenes have good photothermal properties and improve the permeability of the BBB. Du et al 120 engineered 2D ultrathin Nb 2 C nanosheets to chelate metal ions and alleviate oxidative stress. In vitro experiments and theoretical calculations have demonstrated the antioxidant properties of Nb 2 C MXenzyme nanosheets and their specific chelating effect on Cu 2+ .…”