Enantiomer-Dependent Uptake of Chiral Nanoparticles in Macrophages Modulates the Inflammatory Response through the NF-κB Pathway

Infectious inflammation caused by pathogens or environmental pollutants remains a major global health issue. Therefore the development of novel strategies to efficaciously control infectious inflammation is urgently required. Nuclear factor-κB (NF-κB) as the central activator of pro-inflammatory genes plays a pivotal role in infectious inflammation. Here, nanoscale chirality was designed to modulate the inflammatory response through enantiomer-dependent blockade of the NF-κB signaling pathway. Chiral gold nanoparticles (AuNPs) with good cytocompatibility were prepared through a one-pot seedless method under wild conditions, showing efficacious alleviation of lipopolysaccharide (LPS)-induced inflammation in vitro and in vivo only by AuNPs with levorotatory chirality (L-AuNPs) rather than the dextrorotatory enantiomer (D-AuNPs). Mechanism investigation elucidated that lysosomal acidification of macrophages was inhibited through a high cellular uptake of L-AuNPs due to their weak interaction energy with cell membranes. Accordingly, the NF-κB rather than mitogen-activated protein kinase pathway was blocked by L-AuNPs through the selective inhibition of p65 phosphorylation, wherein the nuclear translocation of p65 was simultaneously depressed, so the secretion of pro-inflammatory mediators was reduced significantly. This study suggests that imparting chirality to nanoparticles can provide a novel protocol to efficaciously modulate health risks arising from infectious inflammation by improving the uptake of nanoparticles with anti-inflammatory activity.