LAUSR

Alzheimer's disease (AD) remains an incurable disease as the intricate pathogenesis. The neuropathological hallmarks include extracellular amyloid-β (Aβ) plaques, tau phosphorylation and extensive oxidative stress in neuron, which implicate mutually and 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 BBB, the histidine units in the DPH chelate excess metal ions at the extracellular microenvironment, restraining the formation of Aβ aggregates, and induce the first-stage separation. Then, the remanent system targets to 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 to enhanced synergistic therapeutic effects both in the extracellular and intracellular region of the AD brain. After the treatment 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. This article is protected by copyright. All rights reserved.