Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology

作者：Kim HY, Choi EN, Lee GE, Yoon S, Mun SR, Jung EJ, Kim M, Lim H, Kang YJ, Park WJ, Kwon YT, Park JW · 发表于：Asian journal of pharmaceutical sciences · 年份：2026 · DOI：10.1016/j.ajps.2026.101149 · 研究领域：Autophagy、Gaucher disease、Lysosomal storage diseases、Lysosomal targeting、N-degron pathway、p62/SQSTM1/Sequestosome-1

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by misfolding of lysosomal proteins and their degradation via endoplasmic reticulum-associated degradation (ERAD). Deficiency in LSD-associated enzymes leads to the accumulation of toxic materials within the lysosome. In macroautophagy (hereafter autophagy), autophagic receptors as represented by p62/SQSTM1/Sequestosome-1 collect and deliver their cargoes to the lysosome. Here, we developed the LYSOTAC (LYSOsome-TArgeting Chimera) technology, which enables lysosomal targeting of LSD-associated enzymes while preserving their enzymatic activities. LYSOTAC employs a bifunctional chimera that simultaneously binds an LSD-associated enzyme via the enzyme-binding ligand (EBL) and p62 via the autophagy-targeting ligand (ATL). Upon binding, p62 undergoes self-polymerization to form cargo-p62 complexes, which are sequestered into autophagosomes and delivered to lysosomes, where the enzymes exhibit maximal activity. Here, LYSOTAC compounds targeting β-glucocerebrosidase (GCase) were designed to restore GCase activity in lysosomes and promote glucosylceramide degradation in Gaucher disease fibroblasts. We suggest that LYSOTAC provides a potential therapeutic strategy for LSDs.