Lysosome‐Targeting Protein Degradation Through Endocytosis Pathway Triggered by Polyvalent Nano‐Chimera for AD Therapy

Abstract The excessive up‐regulation of receptor for advanced glycation end products (RAGE), a well‐known pathological marker, drives the onset and progression of Alzheimer's disease. Although lysosome‐targeting protein degradation has emerged as an effective therapeutic modality, the limited lysosome‐sorting efficacy greatly hindered the degradation efficiency of target proteins. Herein, a lysosome‐shuttle‐like nano‐chimera (endoTAC) is proposed based on polyvalent receptor binding mode for enhanced RAGE degradation as well as precise drug delivery. The endoTAC shows a high affinity to RAGE and enhances RAGE degradation due to its polyvalent‐interaction with RAGE. Additionally, endoTAC features increased accumulation in diseased brain and shows promise as a precise brain delivery system. After loading with simvastatin, the SV@endoTAC proves to successfully reverse pathological features both in vitro and in vivo. The work proposes that the combination of a lysosome‐targeting chimera and an effective drug delivery system can be promising in Alzheimer's disease therapy.