Nanomotor‐Driven Targeting Chimeras as Accelerators for the Degradation of Extracellular Proteins

Abstract Targeted protein degradation (TPD) is emerging as a therapeutic paradigm and a serviceable research tool in chemical biology and disease treatment. However, without driving sources, most targeting chimeras (TACs) lack the capability of self‐diffusion and active searching in biological environments, which significantly impedes degradation efficiency. Herein, nanomotor‐driven targeting chimeras (MotorTACs) are ingeniously designed to achieve effective internalization and degradation of extracellular platelet‐derived growth factor (PDGF), a driver to cancer invasion and metastasis. Catalyzed by endogenous H 2 O 2 , MotorTACs diffused rapidly and searched actively in living cells, as visualized at the single‐particle level under the dark‐field mode. Hydrolysis efficiency is significantly enhanced as target protein degradation is complete in only 4 h. Furthermore, MotorTACs‐mediated degradation of PDGF is found to be via the lysosome and ubiquitin‐proteasome dual‐degradation pathways. Taking advantage of the properties, it is anticipated that MotorTACs provide a unique strategy against extracellular undruggable proteins, thus advancing the development of therapeutic interventions in chemical biology and disease treatment.