Size-tailored nanoparticle–antibody conjugates overcome hepatic sequestration in Alzheimer’s disease treatment

Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer’s disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ 42 monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice, intravenous PEG-MSN-1F12 administration markedly enhanced peripheral Aβ clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral Aβ removal further led to decreased brain Aβ deposition, attenuated microglial activation, and improved cognition. These findings highlight that the use of particle size–engineered antibody–nanoparticle conjugates is a safe and effective strategy to overcome hepatic sequestration, augment Aβ clearance, and improve AD outcomes.