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

Abstract

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 noncovalent 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.