Aβ42 and ROS Dual-targeted Multifunctional Nanocomposite for Combination Therapy of Alzheimer’s Disease

Abstract

Abstract Amyloid-β (Aβ) is prone to misfolding into neurotoxic aggregates that generate high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging ROS may be a promising therapeutic strategy for alleviating Alzheimer’s disease pathology. Based on the previously developed antibody 1F12 that can target all forms of Aβ42, we developed an Aβ42 and ROS dual-targeted nanocomposite using biodegradable mesoporous silica nanoparticles as a carrier to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). With the modification of brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system therapy, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ42 misfolding, accelerating Aβ42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ42 and ROS dual-targeted strategy also reduced hyperphosphorylated tau burden, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings suggest that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that facilitates multi-target therapy in AD.