Cleavable Antibody-Conjugated Aβ Specific Immune Exosome for Combination Alzheimer's Disease Immunotherapy.

Recent progress in antibody-based immunotherapies for Alzheimer's disease (AD) brings a sense of cautious optimism after years of setbacks. However, these approaches remain constrained by suboptimal pharmacodynamics, modest clinical benefits, and pro-inflammatory adverse effects. Here, we develop a β-secretase-responsive immunotherapeutic agent (ATExo-cL-aA) that synergistically targets amyloid-β (Aβ) and neuroinflammatory response, achieving heightened efficacy while reducing the side effects associated with conventional antibody therapies. After intranasal administration, ATExo-cL-aA actively migrates to AD brains. Upon cleavage by overexpressed β-secretase, ATExo-cL-aA releases aducanumab antibody (aA) and exosomes derived from Aβ antigen-specific Tregs (ATExo), which jointly manage Aβ and inflammatory microglia, thereby synergistically eradicating Aβ and reducing pro-inflammatory responses. In AD mouse models, ATExo-cL-aA demonstrates efficient brain accumulation, robust Aβ removal, microglial normalization, neuroinflammation attenuation, and synaptic preservation, ultimately leading to improved cognitive function. These findings highlight ATExo-cL-aA as next-generation immunotherapeutics that transcend the limitations of conventional antibody-based treatments for AD.