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The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well\u2010characterized mouse model of Alzheimer's disease. The application of brain\u2010penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid <jats:italic>\u03b2<\/jats:italic> plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging\u2010based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid <jats:italic>\u03b2<\/jats:italic>. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. 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