A high-throughput approach to optimize and understand nanoparticle protein degraders.

Targeted protein degradation strategies have emerged as a promising approach for addressing undruggable membrane proteins by redirecting them to the cell's degradation machinery. Traditionally, this has been achieved through antibody-based constructs that hijack the endocytic pathways. More recently, nanoparticles have been proposed as a modular platform for surface protein scavenging, offering tunable properties and multivalent targeting. However, the extent to which nanoparticle physicochemical features influence degradation efficacy remains to be elucidated. In this study, we set up a high-content imaging workflow to screen a diverse library of antibody-functionalized nanoparticles varying in material composition, size, and targeting modality. Our results reveal that specific combinations of nanoparticle properties induce efficient receptor scavenging, allowing us to understand structure-activity relations better. These findings highlight the complex interplay between nanoparticle design and biological response and demonstrate the value of our high-throughput platform for guiding the rational design of nanoparticle-based protein degraders.