Semisynthetic Ferritin Nanocages for Flexible, Site-Specific Targeting and Ligand-Free Activation of Membrane Receptors

Homopolymerization and cluster formation of cellular membrane receptors (MRs) are increasingly recognized as an essential facet of cell signaling and modulator of physiological responses. Yet, there is a lack of tools that can mediate precise stimulation to better understand the mechanisms and effects of clustering. Here, we designed fluorescent semisynthetic nanoparticles (NPs) based on the iron-storage protein ferritin and Staphylococcus aureus protein A to specifically target and activate distinct MRs, without causing side-effects. The NP exhibits high monodispersity and is readily equipped with a variety of antibodies with a KD value below 5 nM. Specificity of the NP antigen recognition was evaluated for cells expressing transferrin receptor 1 (TfR1) or the death receptor CD95, both of which displayed NP-mediated cluster formation. Finally, our engineered NP acts as a natural ligand for TfR1 and induces apoptosis signaling solely by CD95 cluster formation in a ligand-independent manner.