Multifunctional Gold Nanocluster‐Based PROTAC System for Targeted Degradation of Phosphorylated Tau and Modulation of Neuroinflammation in Alzheimer's Disease

ABSTRACT Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and lacks treatments capable of significantly altering disease progression or patient outcomes. Consequently, novel therapeutic strategies targeting key pathological features such as phosphorylated tau (pTau) aggregation and chronic inflammation are urgently needed. In this work, we present a novel proteolysis‐targeting chimera (PROTAC) system conjugated to lipoic acid gold nanoclusters (PLANC), designed to degrade pTau, regulate inflammatory signaling, and effectively traverse the blood‐brain barrier (BBB). PLANC demonstrated the ability to significantly degrade pTau at various phosphorylation sites, with mechanistic studies confirming proteasome‐mediated degradation via cereblon recruitment. Moreover, PLANC effectively scavenged reactive oxygen species (ROS) and modulated NF‐κB and mTOR pathways in human astrocytes and mature neurons, further highlighting its anti‐inflammatory capabilities. We demonstrated that PLANC successfully traversed the BBB using a physiologically relevant transwell model composed of astrocytes and endothelial cells with confirmed tight junction formation. Finally, the addition of pTau‐induced neurons created a BBB model to better represent changes in the AD environment. Collectively, these findings position PLANC as a robust and multifunctional therapeutic platform capable of simultaneously targeting the multifaceted pathologies of AD, including pTau aggregation, neuroinflammation, and oxidative stress.