Functionalised penetrating peptide-chondroitin sulphate‑gold nanoparticles: Synthesis, characterization, and applications as an anti-Alzheimer's disease drug

The purpose of this study was to construct a transmembrane peptide-chondroitin sulphate‑gold nanoparticle (TAT-CS@Au) delivery system and investigate its activity as an anti-Alzheimer's disease (AD) drug. We successfully prepared TAT-CS@Au nanoparticles, investigated their anti-AD effects, and explored the possible mechanisms in in vitro models. TAT-CS@Au exhibited excellent cellular uptake and transport capacity, effectively inhibited the accumulation of Aβ1-40, and significantly reduced Aβ1-40-induced apoptosis in SH-SY5Y cells. Furthermore, TAT-CS@Au significantly reduced oxidative stress damage and cholinergic injury induced by Aβ1-40 by regulating intracellular concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and acetylcholine (ACh). Western blotting results demonstrated that TAT-CS@Au inhibited aberrant tau phosphorylation (Ser199, Thr205, Ser404, and Ser396) through GSK3β inactivation. TAT-CS@Au decreased the levels of inflammatory factors, specifically TNF-α, IL-6, and IL-1β, by inhibiting NF-κB nuclear translocation by activating MAPK signalling pathways. Overall, these results indicate that TAT-CS@Au exhibits excellent transmembrane ability, inhibits Aβ1-40 accumulation, antagonises oxidative stress, reduces aberrant tau phosphorylation, and suppresses the expression of inflammatory factors. TAT-CS@Au may be a multi-target anti-AD drug with good cell permeability, providing new insights into the design and research of anti-AD therapeutics.