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However, these approaches remain constrained by suboptimal pharmacodynamics, modest clinical benefits, and pro\u2010inflammatory adverse effects. Here, we develop a \u03b2\u2010secretase\u2010responsive immunotherapeutic agent (ATExo\u2010cL\u2010aA) that synergistically targets amyloid\u2010\u03b2 (A\u03b2) and neuroinflammatory response, achieving heightened efficacy while reducing the side effects associated with conventional antibody therapies. After intranasal administration, ATExo\u2010cL\u2010aA actively migrates to AD brains. Upon cleavage by overexpressed \u03b2\u2010secretase, ATExo\u2010cL\u2010aA releases aducanumab antibody (aA) and exosomes derived from A\u03b2 antigen\u2010specific Tregs (ATExo), which jointly manage A\u03b2 and inflammatory microglia, thereby synergistically eradicating A\u03b2 and reducing pro\u2010inflammatory responses. In AD mouse models, ATExo\u2010cL\u2010aA demonstrates efficient brain accumulation, robust A\u03b2 removal, microglial normalization, neuroinflammation attenuation, and synaptic preservation, ultimately leading to improved cognitive function. These findings highlight ATExo\u2010cL\u2010aA as next\u2010generation immunotherapeutics that transcend the limitations of conventional antibody\u2010based treatments for AD.<\/jats:p>","DOI":"10.1002\/anie.202517917","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T06:25:36Z","timestamp":1758954336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cleavable Antibody\u2010Conjugated A\u03b2 Specific Immune Exosome for Combination Alzheimer's Disease Immunotherapy"],"prefix":"10.1002","volume":"64","author":[{"given":"Mengmeng","family":"Ma","sequence":"first","affiliation":[{"name":"School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University  21 Nanyang Link Singapore 637371 Singapore"},{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang 325035 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