Transferrin-KD8 Complex Capture and Cell Nanovesicle-Immobilization Strategy to Prevent Amyloid Protein-Induced Endothelial Leakage in Alzheimer’s Disease

Amyloid protein-induced endothelial leakage (APEL) may promote endothelial dysfunction and enhance Aβ oligomers aggregation, suggesting a potential mechanism in Alzheimer’s disease pathogenesis. Herein, we propose a therapeutic strategy to suppress the APEL effect. The approach involves engineering an Aβ-targeting peptide KD8 conjugated transferrin to selectively capture circulating Aβ oligomers in the bloodstream. Upon the transferrin-peptide-Aβ oligomers formation, the complex is immobilized by transferrin receptor-overexpressing MDA-MB-231 tumor cell membrane-derived nanovesicles through the transferrin receptor. The resulting ″Aβ oligomer-vesicle″ complex exhibits a substantially increased hydrodynamic diameter. This size amplification is hypothesized to mitigate the APEL effect by two potential mechanisms. First, the enlarged complex sizes may exhibit reduced permeability across the intact vascular endothelial barrier. Second, and more critically, the surface immobilization of Aβ oligomers likely imposes significant steric and geometric constraints, impairing their accessibility and binding kinetics to key endothelial targets, such as VE-cadherin. This interference would disrupt the oligomers’ capacity to compromise endothelial tight junctions and initiate leakage. Consequently, this approach aims to systemically reduce the risk of the APEL effect through combined physical sequestration and molecular interference. This mechanism not only prevents the onset of amyloid protein-induced endothelial leakage (APEL) and inhibits further fibril accumulation but also actively promotes the clearance of existing amyloid deposits, underscoring its therapeutic potential for Alzheimer’s disease.