Lipid-Raft-Mediated Direct Cytosolic Delivery of Polymer-Coated Soft Nanoparticles

Polymer shelling around a nanoparticle is commonly employed for stabilization, surface chemistry, and bioconjugation. However, this shelling increases the overall size of the nanoparticle which limits many biomedical applications. Here we show that soft and nonionic polymer shelling can induce direct cytosolic delivery of a nanoparticle, as compared to clathrin-mediated uptake and lysozomal trafficking by a similarly sized nanoparticle with molecular shelling. Specifically, we have studied cellular internalization of two classes of colloidal nanoparticles of 10-50 nm hydrodynamic size. In one class, a 4-5 nm quantum dot is coated with a soft polyacrylate shell of varied thickness between 2 and 20 nm and in the other class a Au nanoparticle of varied size between 5 and 45 nm is coated with a molecular shell. We found that polymer shelling has two roles in controlling cellular internalization of nanoparticles. First, it increases the hydrodynamic size and controls the surface charge that influences the binding to the cell membrane, and 10 nm appears to be the minimum size requirement for such binding. Second, it increases softness that induces membrane penetration and directs cytosolic delivery of the nanoparticle. In particular, a soft and nonionic polymer shell induces lipid-raft-mediated direct cytosolic delivery, but a soft and cationic polymer shell induces clathrin-mediated endocytosis with lysozomal trafficking, like that of a nonionic molecular shell. The observed results can be used to design more effective nanoprobes for controlling intracellular processing.