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

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. Multifunctional brain‐penetrating bioactive manganese dioxide nanoparticles modify brain microenvironment of Alzheimer's disease (AD) by reducing inflammation and oxidative stress and improving vascular blood flow and lymphatic clearance of amyloid. This multitargeted strategy shifts the brain microenvironment toward more favorable conditions for neural function and consequent memory improvement. This study may bridge critical gaps in finding disease‐modifying treatment for neurodegenerative disease.