A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer's disease.

Toxic amyloid-beta (Aß) plaque and harmful inflammation are two leading symptoms of Alzheimer's disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aß fibrils formation, degrades Aß fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.

A Giant Heterometallic Polyoxometalate Nanocluster for Enhanced Brain-Targeted Glioma Therapy.

Giant heterometallic polyoxometalate (POM) clusters with precise atom structures, flexibly adjustable and abundant active sites are promising for constructing functional nanodrugs. However, current POM drugs are almost vacant in orthotopic brain tumor therapy due to the inability to effectively penetrate the blood-brain barrier (BBB) and low drug activity. Here, we designed the largest (3.0 nm × 6.0 nm) transition-metal-lanthanide co-encapsulated POM cluster {[Ce10 Ag6 (DMEA)(H2 O)27 W22 O70 ][B-α-TeW9 O33 ]9 }2 88- featuring 238 metal centers via synergistic coordination between two geometry-unrestricted Ce3+ and Ag+ linkers with tungsten-oxo cluster fragments. This POM was combined with brain-targeted peptide to prepare a brain-targeted nanodrug that could efficiently traverse BBB and target glioma cells. The Ag+ active centers in the nanodrug specifically activate reactive oxygen species to regulate the apoptosis pathway of glioma cells with a low half-maximal inhibitory concentration (5.66 µM). As the first brain-targeted POM drug, it efficiently prolongs the survival of orthotopic glioma-bearing mice.