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

Abstract 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.