Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics

TLDR

In vitro plasma incubation of nanomaterials provides insights into biological interactions but fails to fully explain their in vivo fate. The study uses a library of polymer nanoparticles to demonstrate how physicochemical properties affect blood circulation and early distribution. Using knockout mice, the authors identified clearance mechanisms for nanoparticles with low and high steric protection, revealing how physicochemical characteristics influence circulation. Higher surface hydrophilicity and PEG densities above ~20 chains per 100 nm² prolong circulation, whereas low PEG coverage allows apolipoprotein adsorption to extend circulation, but clearance is driven by the low‑density lipoprotein receptor rather than complement activation, enhancing understanding of nanopharmacology.

Abstract

Abstract In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm 2 prolong circulation times, irrespective of size. In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection. Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles. In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times. In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density. These results further our understanding of nanopharmacology.