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Isomeric Differences in Nanoparticle’s Surface Chemistry Alters Macrophage Interactions In Vitro Due to Protein Corona

ABSTRACT: The interactions of nanoparticles (NPs) with macrophages after intravenous injection are critical in determining their biodistribution and pharmacokinetics. The formation of protein corona (PC) on the nanoparticles, often a result of NP-plasma protein interactions, influences macrophage response, thereby directly determining the NP's fate in vivo. While the effect of NP’s surface chemistry on the protein corona formation and macrophage interaction is extensively studied, the results are often confounded by the effects of surface charge and hydrophobicity. Therefore, to assess the impact of NP’s surface chemistry alone on protein corona and NP-macrophage interactions, we developed gold (Au) NPs surface modified with the isomeric amino acids leucine (Leu) and isoleucine (Iso leu), which have similar isoelectric point and hydropathy indices. The synthesized NPs had similar size, zeta potential, hydrophobicity, and morphology. Incubation of the NPs in plasma under flow conditions resulted in protein corona (PC) that differed in the amount and composition. Pathway analysis showed that these variations in the PC corresponded with the activation of different phagocytic and inflammatory pathways. These in silico analyses were confirmed in macrophages, which showed higher uptake of Leu AuNP-PC complex compared to Iso leu AuNP-PC and a corresponding increase in the inflammatory cytokines. These studies demonstrate the sensitivity of the PC to subtle changes in the surface chemistry of NPs, which could have significant in vivo implications for the clinical application of NPs.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Sridevi Baradhwaj Conjeevaram

LAB HEAD: Isaac Adjei

PROVIDER: PXD051722 | Pride | 2025-10-06

REPOSITORIES: Pride

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Isomeric Differences in Nanoparticle's Surface Chemistry Alter Macrophage Interactions In Vitro Due to Protein Corona.

Conjeevaram Sridevi B SB Kadaba Amulya A Adjei Isaac M IM

ACS omega 20250911 37

The interactions of nanoparticles (NPs) with macrophages after intravenous injection are critical in determining their biodistribution and pharmacokinetics. The formation of protein corona (PC) on the nanoparticles, often a result of NP-plasma protein interactions, influences macrophage response, thereby directly determining the NPs' fate <i>in vivo</i>. While the effect of NPs' surface chemistry on protein corona formation and macrophage interaction is extensively studied, the results are often ...[more]

PMID: 41018626

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Project description:Poly-ethylene-glycol (PEG)-based nanoparticles (NPs) - including cylindrical micelles (CNPs), spherical micelles (SNPs), and PEGylated liposomes (PLs) - are hypothesized to be cleared in vivo by opsonization followed by liver macrophage phagocytosis. This hypothesis has been used to explain the rapid and significant localization of NPs to the liver after administration into the mammalian vasculature. Here, we show that the opsonization-phagocytosis nexus is not the major factor driving PEG-NP – macrophage interactions. First, mouse and human blood proteins had insignificant affinity for PEG-NPs. Second, PEG-NPs bound macrophages in the absence of serum proteins. Third, lipoproteins blocked PEG-NP binding to macrophages. Because of these findings, we tested the postulate that PEG-NPs bind (apo)lipoprotein receptors. Indeed, PEG-NPs triggered an in vitro macrophage transcription program that was similar to that triggered by lipoproteins and different from that triggered by lipopolysaccharide (LPS) and group A Streptococcus. Unlike LPS and pathogens, PLs did not increase transcripts involved in phagocytosis or inflammation. High-density lipoprotein (HDL) and SNPs triggered remarkably similar mouse bone-marrow-derived macrophage transcription programs. Unlike opsonized pathogens, CNPs, SNPs, and PLs lowered macrophage autophagosome levels and either reduced or did not increase the secretion of key macrophage pro-inflammatory cytokines and chemokines. Thus, the sequential opsonization and phagocytosis process is likely a minor aspect of PEG-NP – macrophage interactions. Instead, PEG-NP interactions with (apo)lipoprotein and scavenger receptors appear to be a strong driving force for PEG-NP – macrophage binding, entry, and downstream effects. We hypothesize that the high presence of these receptors on liver macrophages and on liver sinusoidal endothelial cells is the reason PEG-NPs localize rapidly and strongly to the liver. To investigate the response of macrophages to nanoparticles, we incubated PEGylated liposomes (PLs), spherical nanoparticles (SNPs), high-density lipoproteins (HDL), low-density lipoproteins (LDL), Group A Streptococcus pathogens (JRS4), and lipopolysaccharide (LPS) with RAW264.7 and primary bone-marrow derived mouse macrophages

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