θ-Solvent-Mediated Double-Shell Polyethylene Glycol Brushes on Nanoparticles for Improved Stealth Properties and Delivery Efficiency.

Antifouling polymer brushes are widely used to inhibit the formation of protein corona on nanoparticles (NPs) and subsequent accumulation in the liver and spleen. Herein, we demonstrate a θ-solvent-mediated method for the preparation of gold nanoparticles with a high polyethylene glycol (PEG) grafting density. Reaching the θ-solvent by adding salt (e.g., Na2SO4) can significantly increase the grafting density of the PEG brush to 2.08 chains/nm2. The PEG polymer brush prepared in the θ-solvent possesses a double-shell structure consisting of a concentrated polymer brush (CPB) and a semidilute polymer brush (SDPB), denoted as NP@CPB@SDPB, while those prepared in a good solvent have only a SDPB shell, i.e., NP@SDPB. Compared to the NP@SDPB structure, the NP@CPB@SDPB structure decreases the liver accumulation from 34.0%ID/g to 23.1%ID/g, leading to an increase in tumor accumulation from 8.5%ID/g to 12.8%ID/g. This work provides new insights from the perspective of polymer physical chemistry into the improved stealth properties and delivery efficiency of NPs, which will accelerate the clinical translation of nanomedicine.