Macrophage‐Targeted Magnesium Ion‐Nourisher for NLRP3 Inflammasome Inhibition to Enhance Liver Inflammatory Disease Treatment

Abstract Magnesium (Mg) exerts important functions in immune regulation. Fluctuations of Mg levels significantly impact immune cell behavior, such as differentiation and inflammatory phenotypes of macrophages. However, exploiting Mg as an immunomodulatory intervention is challenging due to its unclear mechanism and broad impact across diverse cells. To overcome this, a nanosized Mg ion‐nourisher is engineered, termed MgC ^@PS , that enables efficient macrophage‐targeted intracellular Mg ² ⁺ (iMg ²⁺ ) delivery by exploiting macrophages’ efferocytosis in response to phosphatidylserine. It is found that targeted enrichment of magnesium ions (Mg ² ⁺) into macrophages effectively inhibits NOD‐like receptor pyrin domain containing 3 (NLRP3) inflammasome activation‐induced pyroptosis, and alleviates hyperactive inflammatory responses. Single‐cell RNA sequencing reveals fortified resilience of Kupffer cells from pyroptosis and upregulation of antioxidant gene expression after MgC ^@PS treatment. Moreover, by incorporating stem cell components into the MgC ^@PS , the integrity of the intestinal barrier, addressing the barrier leakage commonly observed in the gut‐liver axis. These findings demonstrate the pivotal role of iMg ² ⁺ in mitigating macrophage‐mediated liver‐gut inflammation. Targeted delivery of Mg to macrophages emerges as a promising strategy to inhibit excessive inflammation and promote tissue recovery.