Gallium Nanodroplets are Anti-Inflammatory without Interfering with Iron Homeostasis

Abstract

Gallium (Ga) compounds, as the source of Ga ions (Ga3+), have been historically used as anti-inflammatories. Currently, the widely accepted mechanisms of the anti-inflammatory effects for Ga3+ are rationalized on the basis of their similarities to ferric ions (Fe3+), which permits Ga3+ to bind with Fe-binding proteins and subsequently disturbs the Fe homeostasis in the immune cells. Here in contrast to the classic views, our study presents the mechanisms of Ga as anti-inflammatory by delivering Ga nanodroplets (GNDs) into lipopolysaccharide-induced macrophages and exploring the processes. The GNDs show a selective inhibition of nitric oxide (NO) production without affecting the accumulation of pro-inflammatory mediators. This is explained by GNDs disrupting the synthesis of inducible NO synthase in the activated macrophages by upregulating the levels of eIF2α phosphorylation, without interfering with the Fe homeostasis. The Fe3+ transferrin receptor-independent endocytosis of GNDs by the cells prompts a fundamentally different mechanism as anti-inflammatories in comparison to that imparted by Ga3+. This study reveals the fundamental molecular basis of GND–macrophage interactions, which may provide additional avenues for the use of Ga for anti-inflammatory and future biomedical and pharmaceutical applications.

Gallium-Based Liquid Metal Materials for Antimicrobial Applications

“…In particular, researchers found that LM antimicrobial agents are not friendly to immunocompromised patients because prolonged use of Ga can lead to reduced immunity [ 134 ]. However, it is worth mentioning that one study has investigated that delivering LM nanodroplets into a macrophage is a potential way to modulate discrete signaling pathways, without interfering with Fe homeostasis from the usage of Ga 3+ [ 135 ]. This study sheds light on the mechanism of LM nanodroplets–macrophage interactions, potentially enabling more pathways for Ga to be used for future biomedical and pharmaceutical applications.…”

Strategies to prevent, curb and eliminate biofilm formation based on the characteristics of various periods in one biofilm life cycle

“…Another recently proposed article of the exact opposite mechanism of anti-inflammatory action of classical Ga ions (Ga3+) via delivering Ga nanodroplets (GNDs) to lipopolysaccharide-induced macrophages. GNDs exerted a selective inhibition of NO generation without interfering with the accumulation of pro-inflammatory agents by disrupting the synthesis of inducible NO synthase in activated macrophages through up-regulation of eIF2α phosphorylation levels, without disturbing Fe homeostasis ( Zhang et al., 2022 ). A lipophilic Ga complex, Ga2L3(bpy)2, has both Ga (disruption of iron metabolism) and ligand effects (production of ROS) in the fight against drug-resistant bacteria ( Wang et al., 2021 ).…”

Assembly of surface-independent polyphenol/liquid gallium composite nanocoatings

“…39 However, the present results essentially provide fundamental insights for the future design of nanocoating using Ga NPs with higher antibacterial activity. Lastly, considering that Ga ions also have an anti-inflammatory effect, 49 such nanocomposites with antioxidant and antibacterial properties have the potential to be applied to a wider range of biomedical applications including medical and implantable devices.…”