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Species disparity and sensitivity differences in opsonization and phagocyte recognition of poly-2-alkyl-2-oxazoline-coated nanoparticles

ABSTRACT: Poly(ethylene glycol) (PEG) is widely used in engineering of clinical nanomedicines; however, the emerging PEG immunogenicity is compromising their therapeutic efficacy. Polyoxazolines are gaining popularity as PEG alternatives, since “polyoxazolination” confers stealthing behaviour to nanomedicines in the preclinical mouse model. Here, using nanoparticles coated with either poly-2-methyl-2-oxazoline (PMOXA) or poly-2-ethyl-2-oxazoline (PEOXA), we show species differences in nanoparticle opsonization and phagocytic cell responses. PMOXA- and PEOXA-coated nanoparticles evade murine serum opsonization and phagocytic clearance. Polyoxazolinated nanoparticles, however, undergo differential opsonization in porcine and human sera, resulting in nanoparticle recognition by different phagocytic cells differently. We identify ficolin 2 (FCN2) as a monocyte-specific opsonin in pigs, whereas in human sera, FCN opsonization is isoform-dependent with inter-individual variability. Polymer recognition is through the S2 domain of FCN2 which sense hydrogen bond forming chemical moieties and hydrophobic patterns of polyoxazolines. Contrary to the porcine model, both FCN2 and complement promote nanoparticle uptake by human monocytes. On the other hand, nanoparticle uptake by human and porcine macrophage is complement-dependent. These findings highlight the importance of species differences in innate immune recognition of nanomaterials’ molecular patterns, and are relevant to the selection and chemical design of polymers for engineering of the next generation of stealth nanoparticles.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human) Sus Scrofa Domesticus (domestic Pig) Mus Musculus (mouse)

TISSUE(S): Blood Plasma

SUBMITTER: Giorgio Arrigoni

LAB HEAD: Giorgio Arrigoni

PROVIDER: PXD058735 | Pride | 2025-03-11

REPOSITORIES: Pride

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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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	05May2016_PEG.raw	Raw
	05May2016_PEG_EDTA.raw	Raw

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Species disparity and sensitivity differences in opsonization and phagocyte recognition of poly-2-alkyl-2-oxazoline-coated nanoparticles

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