Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation

Abstract

This study shows that supramolecular arrangement of proteins in nanoparticle structure predicts nanoparticle accumulation in neutrophils in acute lung inflammation (ALI). We observed homing to inflamed lungs for a variety of n anoparticles with a gglutinated p rotein (NAPs), defined by arrangement of protein in or on the nanoparticles via; a) hydrophobic interactions; b) crosslinking; c) electrostatic interactions. Nanoparticles with symmetric protein arrangement ( e.g. , viral capsids) had no selectivity for inflamed lungs. Flow cytometry and immunohistochemistry showed NAPs have tropism for pulmonary neutrophils. Protein-conjugated liposomes were engineered to recapitulate NAP tropism for pulmonary neutrophils. NAP uptake in neutrophils was shown to depend on complement opsonization. We; a) demonstrate diagnostic imaging of ALI with NAPs; b) show NAP tropism for inflamed human donor lungs; c) show NAPs can remediate pulmonary edema in ALI. This work demonstrates structure-dependent tropism for neutrophils drives NAPs to inflamed lungs and shows NAPs can detect and treat ALI.

Albumin Nanoparticle Endocytosing Subset of Neutrophils for Precision Therapeutic Targeting of Inflammatory Tissue Injury

“…Moreover, it has not been addressed whether these nanoparticle preparations interfere with host antimicrobial function. 60 By contrast, our data indicate that ANP are suitable drug delivery vehicles that do not interfere with antibacterial host function. It has also been shown that incorporation of denatured albumin beads by neutrophils depends on Mac-1 expression, 61 whereas ANP endocytosis is Mac-1-independent and requires CD16, 27 suggesting distinct molecular mechanisms for endocytosis of albumin nanoparticles.…”

“… 59 The concept of targeting neutrophils for diagnostic or therapeutic purposes has recently been further validated. 60 Using a supramolecular arrangement of protein in or on nanoparticles, another group described a different way for targeting neutrophils. 60 While these nanoparticle preparations showed tropism for pulmonary neutrophils, their specificity for neutrophils or whether they would target functionally distinct neutrophil subsets has not been reported.…”

“… 60 Using a supramolecular arrangement of protein in or on nanoparticles, another group described a different way for targeting neutrophils. 60 While these nanoparticle preparations showed tropism for pulmonary neutrophils, their specificity for neutrophils or whether they would target functionally distinct neutrophil subsets has not been reported. 60 Some of these nanoparticle preparations showed intrinsic anti-inflammatory effects, 60 potentially complicating their use as drug delivery platforms.…”

“… 60 While these nanoparticle preparations showed tropism for pulmonary neutrophils, their specificity for neutrophils or whether they would target functionally distinct neutrophil subsets has not been reported. 60 Some of these nanoparticle preparations showed intrinsic anti-inflammatory effects, 60 potentially complicating their use as drug delivery platforms. Moreover, it has not been addressed whether these nanoparticle preparations interfere with host antimicrobial function.…”

Bioimaging guided pharmaceutical evaluations of nanomedicines for clinical translations

“…Particle size, shape, and surface chemistry are key factors governing the performance criteria, including the degree of protein adsorption, cellular uptake, biodistribution patterns, and clearance mechanisms [ 8 ]. NMs have the potential to be precisely designed by tuning these factors to achieve individualized and more efficient treatment and diagnostic agents while minimizing potential side effects [ 9 , 10 ]. As the NMs landscape evolves, it is increasingly important to understand the intrinsic connection between the structural and functional relationship, which allows the further optimization and manipulation of fine nanostructures to meet general standards, applicable to medicinal compounds.…”