Autonomously Motile Nano‐PROTACs Act as Protein‐Sweeping Robots to Enhance Targeted Protein Degradation

Abstract

ABSTRACT Although nanoparticle‐based PROTACs (nPROs) provide a modular strategy to improve the biological fate of PROTACs, their degradation performance was fundamentally limited by restricted intracellular diffusivity. Here, we introduced an unconventional solution: Imparting autonomous motility to nPROs to transform them from passive carriers into active protein‐seeking degraders. We engineered nano‐motoring PROTACs (nMPROs) through asymmetric modification of gold nanoparticles, displaying POI ligands and E3 recruiters on one hemisphere while anchoring catalase on the opposite hemisphere. Within the H 2 O 2 ‐rich tumor cell microenvironment, catalase‐generated oxygen fueled directional propulsion, enabling nMPROs to actively navigate the intracellular space rather than relying on random diffusion. This propulsion fundamentally enhanced intracellular target‐search efficiency: nMPROs function as “nanoscopic protein‐sweeping robots,” autonomously interrogating a larger intracellular landscape and capturing more sparsely distributed target proteins. As a result, nMPROs achieved a threefold increase in ERα degradation potency relative to static nPROs and enabled modular, ligand exchange–based degradation of PD‐L1, demonstrating platform generality. Overall, this work establishes a new mechanistic paradigm for enhancing targeted protein degradation of nPROs and lays the foundation for generalizable next‐generation PROTAC nanoplatforms.