Link between Low-Fouling and Stealth: A Whole Blood Biomolecular Corona and Cellular Association Analysis on Nanoengineered Particles

Abstract

Upon exposure to human blood, nanoengineered particles interact with a multitude of plasma components, resulting in the formation of a biomolecular corona. This corona modulates downstream biological responses, including recognition by and association with human immune cells. Considerable research effort has been directed toward the design of materials that can demonstrate a low affinity for various proteins (low-fouling materials) and materials that can exhibit low association with human immune cells (stealth materials). An implicit assumption common to bio–nano research is that nanoengineered particles that are low-fouling will also exhibit stealth. Herein, we investigated the link between the low-fouling properties of a particle and its propensity for stealth in whole human blood. High-fouling mesoporous silica (MS) particles and low-fouling zwitterionic poly­(2-methacryloyloxyethyl phosphorylcholine) (PMPC) particles were synthesized, and their interaction with blood components was assessed before and after precoating with serum albumin, immunoglobulin G, or complement protein C1q. We performed an in-depth proteomics characterization of the biomolecular corona that both identifies specific proteins and measures their relative abundance. This was compared with observations from a whole blood association assay that identified with which cell type each particle system associates. PMPC-based particles displayed reduced association both with cells and with serum proteins compared with MS-based particles. Furthermore, the enrichment of specific proteins within the biomolecular corona was found to correlate with association with specific cell types. This study demonstrates how the low-fouling properties of a material are indicative of its stealth with respect to immune cell association.

Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association

“…Upon exposure to biofluids, the NPs acquire a "protein corona" due to the adherence of host proteins on the NPs surface. The composition of the corona is dependent on the types of nanoparticles and the biological sources [1][2][3] , and considered to provide the NPs with a "biological" identity 4 that affects stability, circulation time, and cellular uptake/interactions, and therefore has a strong impact on the functional role for the NPs [5][6][7][8][9][10] .…”

Cellular Interactions of Liposomes and PISA Nanoparticles during Human Blood Flow in a Microvascular Network

“…Proteins in human blood were found to form a corona on the surface of nanoparticles, likely contributing to their enhanced association with B cells. [ 23 ] In contrast, cells exhibiting a lower association with nanoparticles (e.g., neutrophils and monocytes) had a marked decrease in cellular interaction under flow conditions (Figure 3B). We speculate that the shear force of blood flow may be strong enough to detach a proportion of nanoparticles possessing weak cellular interactions with neutrophils and monocytes but not sufficient to reduce the stronger associations between nanoparticles and B cells.…”

“…In particular, human blood is composed of plasma (containing salts, lipids, proteins, vitamins, hormones, and water) and importantly, a variety of cell types (e.g., monocytes, neutrophils, B cells, dendritic cells (DCs), T cells, and natural killer (NK) cells). [ 22–24 ] In addition, the shear rate of human blood flow varies widely as human blood vessels have a very complex geometry (not straight vessels). [ 25 ] Therefore, to analyze cellular interactions of nanoparticles in blood vessels, three key requirements should be considered.…”

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

“…It includes immunoglobulins, components of the complement system (Vu et al, 2019), coagulation factors and a plethora of other molecules, which fundamentally influences how cells perceive the coated particles (Giulimondi et al, 2019). It is now becoming increasingly appreciated that PEG alters the composition of the biocorona, which consequently influences cellular interactions and uptake modalities (Pelaz et al, 2015;Schöttler et al, 2016;Weiss et al, 2019). Notably, PEGylation is not a guaranteed way to raise biocompatibility, but its effect depends on the underlying material.…”