Responsive Plasmonic Reporters Decrypt Nanoparticle-Induced Single Membrane Protein Degradation

Nanoparticle-mediated degradation of proteins of interest has recently emerged as a powerful tool in biomedical research and the pharmaceutical industry. Nevertheless, the limited understanding of dynamic processes poses challenges in further improving the efficacy. Herein, we develop responsive plasmonic nanoprobe systems capable of discrimination between membrane protein monomer and dimerization states, enabling the direct observation of membrane protein degradation during nanoparticle endocytosis. The nanoprobes are engineered with precisely controlled aptamer modifications through asymmetric spherical nucleic acid functionalization to ensure low-valence protein binding. Upon ligand stimulation, protein dimerization triggers proximity-induced DNA hybridization between nanoprobe and protein complexes, resulting in distinctive plasmonic coupling signals. Using the cellular mesenchymal to epithelial transition factor (Met) as a model protein, we demonstrate differential endocytosis kinetics between monomeric and dimeric states, with dimers exhibiting enhanced endocytic efficiency. Further investigation into downstream protein expression and cellular responses reveals an enhanced phosphorylated Met (p-Met) degradation process by the aggregation state, providing insights into the relationship between protein oligomerization and nanoparticle-mediated degradation efficiency. These findings offer valuable theoretical foundations for designing targeted protein degradation platforms based on nanoparticles.