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

• 成果类型: Article
• 署名作者: Du, Xuewei; Liu, Ni; Zhang, Taoping; Yang, Changwen; Luo, Haiming
• 署名单位: Hainan University; Huazhong University of Science & Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2603034123
• 发表日期: 2026-09-15
• 页码: e2603034123
• 关键词: Alzheimer's disease; amyloid-beta; mesoporous silica nanoparticles; antibody; liver dysfunction; complement

摘要

Antibody-based immunotherapy targeting amyloid-beta (A beta) 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-A beta 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 A beta clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral A beta removal further led to decreased brain A beta 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 A beta clearance, and improve AD outcomes.