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

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 H₂O₂-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.