Supramolecular Host-Guest Assemblies for Tunable and Modular Lysosome-Targeting Protein Degradation

Abstract

Heterobifunctional drugs have revolutionized chemical biology and therapeutic innovation, yet their fixed covalent linkages constrain dynamic adaptability. Here, we introduce Host-Guest Bridged Lysosome-Targeting Chimeras (HGTACs), a supramolecular bifunctional platform that utilizes β-cyclodextrin-adamantane host-guest interactions to achieve tunable and modular assembly. HGTACs effectively facilitated lysosomal degradation of both extracellular and transmembrane proteins, including NS-650, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2. By deconstructing lysosome-targeting chimeras into host and guest components, HGTACs enable spatiotemporal control over protein degradation through non-covalent bridging. This strategy allows for the fine-tuning of degradation efficiency by adjusting stoichiometric ratios and introducing competitive ligands. Notably, the recyclable nature of the asialoglycoprotein receptor-binding host module conferred sustained degradation activity. In vivo, EGFR-targeting HGTACs significantly reduced EGFR protein levels and suppressed tumor growth in xenograft models. This supramolecular control system reshapes lysosome-targeting chimeras, providing a flexible and efficient strategy for advancing chemically induced proximity-based modalities.