Brain‐Penetrating and Disease Site‐Targeting Manganese Dioxide‐Polymer‐Lipid Hybrid Nanoparticles Remodel Microenvironment of Alzheimer's Disease by Regulating Multiple Pathological Pathways

Abstract

Finding effective disease‐modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well‐characterized mouse model of Alzheimer's disease. The application of brain‐penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid β plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging‐based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid β. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease‐modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

Manganese Dioxide-Based Nanomaterials for Medical Applications

“…Recent studies have explored MnO 2 NPs that target several key pathological signaling pathways. MnO 2 NPs and anti-Aβ antibodies were coupled to the brain-targeted terpolymer (TP) to form Ab-TP-MDNPs (Figure C, a) . After Ab-TP-MDNP treatment, the levels of hypoxia markers (e.g., CA9 and HIF-1α) in AD mice were significantly decreased (Figure C, b), and protein and lipid oxidative damage were also reduced, indicating that Ab-TP-MDNPs alleviate hypoxia and oxidative stress.…”

“…(a) Multifunctional mechanism of Ab-TP-MDNPs in the remodeling of the AD brain microenvironment; (b) levels of carbonic anhydrase 9 (CA9) as measured by enzyme-linked immunosorbent assay in AD brain homogenates; (c) cerebral blood flow in the cortex and subcortex with either Aβ-TP-MDNPs (NPs) or vehicle (Veh); (d) results of a fear conditioning test performed at 6 months of age. Reproduced from ref . Available under a CC BY 4.0 DEED license.…”

Advances in the application of manganese dioxide and its composites for theranostics

“…In addition, some studies have confirmed the use of manganese dioxide for treating Alzheimer's disease. E. Park et al 116 utilized multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve imaging and therapeutic benefits in a well-characterized mouse model of Alzheimer's disease (Fig. 6a).…”

“…6 (a) FAIR-FISP magnetic resonance imaging was used to image blood flow in the cerebral cortex and subcortex in the brains of mice with advanced AD. 116 Copyright 2023, Wiley-VCH. (b) Schematic of BM NPs for in vivo MR imaging of BBB permeability and for forecasting the transition of bleeding in the MCAO rat model.…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…[118][119][120] In recent times, extensive research has been conducted on metal oxide low-dimensional nanomaterials possessing the capability to scavenge free radicals. These nanomaterials hold promise for the treatment of diverse oxidative stressrelated conditions, including diseases such as Alzheimer's disease, with Aluminum oxide nanoparticles (Al 2 O 3 NPs) being one of the prominent examples, [121] Iron oxide nanoparticles (Fe 3 O 4 NPs), [121] Yttrium oxide nanoparticles (Y 2 O 3 NPs), [121] Cobalt oxide nanoparticles (Co 3 O 4 NPs), [121] Manganese oxide nanoparticles (Mn 3 O 4 NPs), [36] Ab-TP-MDNPs [122] and so on.…”