The incorporation of valine residues into the polypeptide coatings significantly reduced the macrophage uptake of the nanoparticles, which was not observed for the nanoparticles modified with other amino acid residues like leucine, phenylalanine, isoleucine, and norvaline.

Comprehensive Summary

The structural and surface properties of nanomedicines play an important role in determining their biological fate. Surface chemistry of nanomedicines is one of the key parameters, where researchers used various strategies such as PEGylation to avoid the undesired clearance of nanoparticles (NPs) for enhanced targeting effect. Nevertheless, the fine-tuning of surface chemistry through polymer functionalization remains largely unexplored. In this concise report, we find that the incorporation of only 10 mol% valine residues into the surface-anchored poly(_L-glutamic acid) significantly lowered the macrophage uptake of NPs. The introduction of other hydrophobic amino acid residues, however, increased the NPs internalization instead. The chirality and the side-chain structure of valine played an important role in the unexpected uptake behavior. We believe this work highlights the impact of slight changes of the surface-anchored polymer structure on the behavior of NPs, drawing people's attention to the careful design of surface chemistry to optimize the nanomedicine design.