Gallium Nanodroplets for Anti-Inflammatory Without Interfering with Iron Homeostasis

Gallium (Ga) compounds, as the source of Ga ions (Ga³⁺), have historically used for anti-inflammatory. Currently, the widely accepted mechanisms of the anti-inflammatory effects for Ga³⁺ are rationalized based on 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 an unexpected mechanism of Ga for anti-inflammatory by delivering low dimensional Ga nanodroplets (GNDs) into lipopolysaccharide-induced macrophages and exploring the processes. Surprisingly, 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 induced macrophages, without interfering with the Fe homeostasis. We demonstrate that this is due to the direct uptake of GNDs by the cells, without relying on the Fe³⁺ transferrin receptor-mediated endocytosis, prompting a fundamentally different mechanism from that imparted by Ga³⁺. This study reveals the fundamental molecular basis of GND-macrophage interactions, which offers a base for innovative use of Ga for anti-inflammatory, and future biomedical and pharmaceutical applications.