Biomarker-activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils

Selective degradation of extracellular pathogenic proteins by degrader technologies such as lysosome-targeting chimeras (LYATCs) provides promising therapeutic strategies for "undruggable" targets. However, unsatisfactory blood-brain barrier (BBB) permeability, potential off-target effects, and impaired protein degradation systems limit their therapeutic applications in neurodegenerative diseases. Here, we design, synthesize, and select Pittsburgh compound B (PiB)-derived suitable chimera molecules and then construct multifunctional polydopamine-based LYTACs (KPLYs) with BBB permeability and activatable β-amyloid (Aβ) degradation ability used for Alzheimer's disease (AD) treatment. In AD lesion areas, Aβ degrader cli-LYTACs are synthesized in situ through Aβ-Cu-catalyzed bioorthogonal reactions. Activated cli-LYTACs induce the spatial proximity between Aβ and lysosomal shuttling receptor CD206, which results in the lysosomal trafficking and degradation of Aβ aggregates. Moreover, biocompatible polydopamine can scavenge ROS, suppress inflammation, and promote microglia M2-like polarization. Therefore, KPLYs increase cell surface CD206 expression and restore lysosomal proteolytic function, two determinants of LYTAC effectiveness.