Multiscale NIR-II Imaging-Guided Brain-Targeted Drug Delivery Using Engineered Cell Membrane Nanoformulation for Alzheimer’s Disease Therapy
Dehua Huang, Qianwu Wang, Qianwu Wang, Yuheng Cao, Hongchao Yang, Meng Li, Feng Wu, Yejun Zhang, Guangcun Chen, Qiangbin Wang, Qiangbin Wang
Abstract
Effective drug delivery in the central nervous system (CNS) needs to have long blood-circulation half-lives, to pass through the blood-brain barrier (BBB), and subsequently to be taken up by target cells. Herein, a traceable CNS delivery nanoformulation (RVG-NV-NPs) is developed by encapsulating bexarotene (Bex) and AgAuSe quantum dots (QDs) within Lamp2b-RVG-overexpressed neural stem cell (NSC) membranes. The high-fidelity near-infrared-II imaging by AgAuSe QDs offers a possibility of in vivo monitoring the multiscale delivery process of the nanoformulation from the whole-body to the single-cell scale. It was revealed the synergy of acetylcholine receptor-targeting of RVG and the natural brain-homing and low immunogenicity of NSC membranes prolong the blood circulation, facilitate BBB crossing and nerve cell targeting of RVG-NV-NPs. Thus, in Alzheimer's disease (AD) mice, the intravenous delivery of as low as 0.5% of oral dose Bex showed highly effective up-regulation of the apolipoprotein E expression, resulting rapid alleviation of ∼40% β-amyloid (Aβ) level in the brain interstitial fluid after a single dose administration. The pathological progression of Aβ in AD mice is completely suppressed during a 1 month treatment, thus effectively protecting neurons from Aβ-induced apoptosis and maintaining the cognitive abilities of AD mice.