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

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 HO, 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.