A multifunctional theranostic agent based on rhodamine-modified copper-gallic acid nanoparticles targeting Alzheimer’s β‑amyloid species

The study develops a multifunctional theranostic agent targeting β-amyloid protein (Aβ) oligomers by combining copper-gallic acid nanoparticles with rhodamine . The blood–brain barrier-penetrating nanoparticles can rescue cognitive impairment of Alzheimer’s disease (AD) mice via inhibiting Aβ fibrillization, scavenging reactive oxygen species , and mitigating neuroinflammation , thus presenting promise in AD theranostics. • A theranostic agent (Rho4@Cu-GA NPs) targeting β‑amyloid oligomers is constructed. • Rho4@Cu-GA NPs detect Aβ species and alleviate cognition deficit of transgenic mice. • Rho4@Cu-GA NPs mitigate oxidative stress and neuroinflammation. • Rho4@Cu-GA NPs exhibit promise for early diagnosis and multi-target therapy of AD. β-Amyloid protein (Aβ) fibrillogenesis accompanied by the accumulation of reactive oxygen species (ROS) and neuroinflammation is an imperative cascade event during Alzheimer’s disease (AD) progression. However, effective diagnosis and therapy for AD remain a major challenge due to low detection sensitivity, weak Aβ inhibitory potency, and lack of multi-target intervention modality. To address these, a multifunctional theranostic agent that targets Aβ species is proposed by coordinating copper-gallic acid nanoparticles (Cu-GA NPs) with rhodamine derivative (Rho4). Such elaborately constructed Rho4-modified nanoparticles (Rho4@Cu-GA NPs) show excellent fluorescent detection capabilities toward Aβ species, with a detection limit of 59 nM toward Aβ oligomers. Rho4@Cu-GA NPs effectively inhibit Aβ fibrillogenesis via multivalent interactions and alleviate Aβ-induced cytotoxicity and apoptosis. Meanwhile, Rho4@Cu-GA NPs exhibit superior ROS scavenging capabilities, thus mitigating neuronal oxidative stress triggered by Aβ and ROS and downregulating neuroinflammatory cytokines secreted by microglial cells. In vivo assays with transgenic AD mice demonstrate that Rho4@Cu-GA NPs can penetrate the blood–brain barrier, illuminate Aβ deposits, reduce Aβ plaque deposition, and improve cognition deficits. Therefore, this protocol triggered the combination of early diagnosis and multi-target therapy of AD, which would give deep insight into the development of potent AD theranostic agents.