Site‐Specific and Regioselective Modification of Human Epidermal Growth Factor Receptor 2 via Site‐Sculpted DNA Nanorefiners

The site-specific modification of native proteins is essential for regulating their functions and behaviors in biological systems. Such modifications enable advanced studies, but existing artificial methods often lack site selectivity and may perturb the functional integrity of the native proteins. In this study, we have developed a programmable platform based on site-sculpted DNA nanorefiners (SS-DNRs), which enables site-specific modifications of proteins at multiple spatially defined sites through precise molecular recognition. Using the human epidermal growth factor receptor 2 (HER2) as a model system, we demonstrate that this approach could achieve precise site-specific and regioselective modifications at multiple distinct sites without perturbing its intrinsic activity. By leveraging the programmability and addressability of DNA nanostructures, our platform effectively addresses fundamental challenges related to molecular selectivity and site selectivity that are inherent in chemical, enzymatic, genetic, and affinity-based modification strategies.