Structural Design of Multidentate Copolymers as Compact Quantum Dot Coatings for Live-Cell Single-Particle Imaging

Quantum dots (QDs) are a class of semiconductor nanocrystal used broadly as fluorescent emitters for analytical studies in the life sciences. These nanomaterials are particularly valuable for single-particle imaging and tracking applications in cells and tissues. An ongoing technological goal is to reduce the hydrodynamic size of QDs to enhance access to sterically hindered biological targets. Multidentate polymer coatings are a focus of these efforts and have resulted in compact and stable QDs with hydrodynamic diameters near 10 nm. New developments are needed to reach smaller sizes to further enhance transport through pores in cells and tissues. Here, we describe how structural characteristics of linear multidentate copolymers determine hydrodynamic size, colloidal stability, and biomolecular interactions of coated QDs. We tune copolymer composition, degree of polymerization, and hydrophilic group length, and coat polymers on CdSe and (core)shell (HgCdSe)CdZnS QDs. We find that a broad range of polymer structures and compositions yield stable colloidal dispersions; however, hydrodynamic size minimization and nonspecific binding resistance can only be simultaneously achieved within a narrow range of properties, requiring short polymers, balanced compositions, and small nanocrystals. In quantitative single-molecule imaging assays in synapses of live neurons, size reduction progressively increases labeling specificity of neurotransmitter receptors. Our findings provide a design roadmap to next-generation QDs with sizes approaching fluorescent protein labels that are the standard of many live-cell biomolecular studies.