Cascade-targeting multifunctional nanochaperone remodels brain microenvironment for synergistic therapy of Alzheimer’s disease

Abstract

The development of a cure for Alzheimer’s disease (AD) has been hindered by complicated pathologies in brain microenvironment, including β-amyloid protein (Aβ) deposition, metal ion dyshomeostasis and excessive oxidative stress. Moreover, the low blood-brain barrier (BBB) penetration and lack AD locus selectivity further limited disease-modifying efficacy of current AD drugs. Herein, we report the design of cascade-targeting multifunctional nanochaperone to remodel brain microenvironment for synergistic treatment of AD. With the cascade mediation of BBB-targeting and AD lesion-targeting peptides modified on surface, the nanochaperone can efficiently penetrate the BBB and selectively accumulate in the AD nidus with abundant Aβ deposits after intravenous administration. More importantly, the brain-arrived nanochaperone can simultaneously promote Aβ aggregates clearance, modulate metal ion homeostasis and scavenge reactive oxygen species (ROS) through the synergic effect of chaperone-mimicking microdomains on surface and functional small-molecule drugs encapsulated in core, thereby achieving multi-target therapy to deal with the complex pathologies in AD microenvironment. After treatment with this multifunctional nanochaperone, the neuron damages and cognitive deficits of APP/PS1 transgenic AD mice are significantly relieved in the brain. Therefore, this work represents a promising candidate for comprehensive treatment of AD and provides new perspectives in the development of drugs for other neurodegenerative disorders.