"Cascaded Rocket" Nanosystems with Spatiotemporal Separation for Triple-Synergistic Therapy of Alzheimer's Disease

Alzheimer's disease (AD) remains an incurable disease due to the intricate pathogenesis. The neuropathological hallmarks include extracellular amyloid-β (Aβ) plaques, tau phosphorylation and extensive oxidative stress in neurons, which facilitate the progression of AD. Based on the complex etiology, a spatiotemporally "cascaded rocket" delivery system (DPH/TPGAS NPs) with metal ion/enzyme responses is established in this study for triple-synergistic AD treatment. After targeting and permeating the blood-brain barrier (BBB), the histidine units in the DPH chelate excess metal ions at the extracellular microenvironment, restraining the formation of Aβ aggregates, inducing the first-stage separation. Then, the remanent system targets neuronal cells and triggers the second separation with cathepsin B for reducing the level of phosphorylated tau and oxidative stress. Accordingly, the DPH/TPGAS NPs can achieve spatiotemporal drug release, which results in enhanced synergistic therapeutic effects both in the extracellular and intracellular region of the AD brain. After treating with DPH/TPGAS NPs, the memory deficits, levels of Aβ and phosphorylated tau, inflammation and neuron damages are remarkably ameliorated in 3 × Tg-AD mice. Therefore, this "cascaded rocket" delivery system has great potential to serve as a powerful platform and provides a new horizon to the therapeutic strategy for AD and other brain diseases' treatments.