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.