Exploring Maleimide-Based Nanoparticle Surface Engineering to Control Cellular Interactions

Nanoparticle cellular interactions are governed by nanoparticle surface chemistry and the surface display of functional (bio)molecules. To conjugate and display thiol-containing (bio)molecules on nanoparticle surfaces, reactions between thiols and functional maleimide groups are often exploited. However, current procedures for modifying nanoparticle surfaces with maleimide groups are complex and can result in nanoparticle aggregation. Here, we demonstrate a straightforward, fast (∼30 min), efficient, and robust one-step surface engineering protocol for modifying gold nanoparticles with functional maleimide groups. We designed a hetero-bifunctional poly(ethylene glycol)-based molecule that attaches efficiently to the gold nanoparticle surface in a single step via its orthopyridyl disulfide (OPSS) terminal end, leaving its maleimide functional group available for downstream reaction with thiols. Using this surface engineering approach, we fabricated gold nanoparticles with near neutral and positive surface charges, respectively. We demonstrate that nanoparticle cellular uptake efficiencies in model mouse breast cancer (4T1) cells, human breast cancer (MDA-MB-231) cells, and human umbilical vein endothelial (HUVEC) cells in tissue culture can be tuned by up to 3 orders of magnitude by adjusting nanoparticle surface chemistry. Our straightforward and efficient maleimide-based nanoparticle surface engineering protocol creates a platform technology for controlled covalent surface attachment of a variety of thiol-containing (bio)molecules to nanoparticles for rational design of nanomaterials with precise cellular interactions for widespread applications in bioanalysis and nanomedicine.