Development of a novel exosome-based nano-scavenger for targeted Amyloid-beta removal - PROJECT SUMMARY Development of a novel exosome-based nano-scavenger for targeted Amyloid- beta removal Objective: To develop a novel exosome-based nano-scavenger (EBNS) for the targeted removal of amyloid-beta (Aβ) proteins, offering a transformative therapeutic strategy for Alzheimer’s disease (AD) and other amyloid-related disorders. Background: Alzheimer’s disease, the leading cause of dementia among the elderly, is characterized by the buildup of toxic Aβ proteins in the brain. Current AD treatments focus on symptom management and Aβ-neutralizing therapies using recombinant human antibodies. However, in addition to their side-effects, these antibody therapies are costly, offer limited benefits in early stages, and are ineffective in late stages due to their inability to clear existing plaques and poor bioavailability. Innovation: Exosomes, cell-derived nano-vesicles, are pivotal in cell-to-cell communication and can transport various macromolecules, including proteins, enzymes, and nucleic acids. Their intrinsic tissue-penetrating ability positions exosomes as a promising class of nanomedicines for neurological targets. Compared to conventional nano-vesicles like liposomes, exosomes offer superior stability, biocompatibility, bioavailability, disease targeting programmability, and high protein loading capacity. However, a significant challenge remains in engineering exosomes to load both disease-targeting antibodies and amyloid-ddegrading enzymes. Research Plan: We propose to develop an EBNS for targeted amyloid removal with the following three specific aims: (1) Genetic engineering: Develop genetic strategies to load Aβ-targeting antibodis and Aβ-degrading enzymes onto exosomes via an exosome-specific anchoring scaffold in human cells. Determine the molecular pathways for exosome targeting and cargo delivery using advanced molecular imaging techniques. (2) Isolation and characterization: Establish procedures for the isolation and purification of exosomes. Characterize the physical, biochemical, and biological properties of the isolated exosomes and evaluate their ability to target and clear Aβ amyloids. (3) Production and evaluation: Produce therapeutic quality of EBNS from selected source cells such as mesenchymal stem cells and 293Tcells. Develop assays to exam the targeting and degrading abilities of the scavenger exosomes. Evaluate their safety and efficacy through molecular and cellular assays. Expected Outcomes: The successful completion of this study is expected to create a novel EBNS system capable of targeted degrading of Aβ plaques, providing a promising new treatment for AD. Additionally, this EBNS has the potential to be adapted for the development of similar nanomedicine for other amyloid-related disorders.
