Influence of structural dynamics on cell uptake investigated with single-chain polymeric nanoparticles

Most nanoparticles' parameters affect their interactions with cells. To date, all the parameters studied are basically static (e.g., size, shape, ligands, and charge). This is unfortunate, because proteins have struc-tural dynamics that most nanoparticles do not possess. Here, we study single-chain polymeric nanoparticles (SCPNs), whose structures un-dergo dynamic changes. We produced multiple sets of particles from identical polymer chains via a supramolecular reshuffling approach that allowed iterative reshuffling between a compact/static and a sparse/dynamic form. These particles are topological isomers because they have identical molecular formulas differing in connectivity and thus structural dynamics. We show that cell uptake discriminates be-tween these SCPN topological isomers. Through different endocytic pathways, the sparse/dynamic isomers are uptaken more, but the compact/static isomers access the cytosol more efficiently, as evi-denced by a glucocorticoid translocation assay. These results highlight the importance of structural dynamics' role in cellular interactions.