Gold Nanocage‐Based Dual Responsive “Caged Metal Chelator” Release System: Noninvasive Remote Control with Near Infrared for Potential Treatment of Alzheimer's Disease

Metal ions have been demonstrated to participate in the pathology of Alzheimer's disease (AD): amyloid‐β peptide (Aβ) aggregation and formation of neurotoxic reactive oxygen species (ROS), such as H₂O₂. Metal chelator can block ROS formation and inhibit metal induced Aβ aggregation. Metal‐ion chelation therapy as a compelling treatment for AD has been extensively studied. However, most chelators are not suitable for AD treatment because of their poor permeability of the blood–brain barrier and their limited ability to differentiate toxic metals associated with Aβ plaques from those associated with normal metal homeostasis. Here, a novel dual‐responsive “caged metal chelator” release system based on gold nanocage (AuNC) for AD treatment is reported. Since arylboronic ester is redox‐ and thermal‐sensitive, phenylboronic acid‐functionalized AuNC can serve as an efficient delivery system for H₂O₂‐responsive controlled release of metal chelator. The release can be further enhanced through remote control with NIR light because of the high near‐infrared absorbance of AuNC. The smart system can effectively inhibit Aβ aggregate formation, decrease cellular ROS, and protect cells from Aβ‐related toxicity. In light of these advantages, this design provides new insights into noninvasive remote control with NIR to improve therapeutic efficacy for treatment of Alzheimer's disease.