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

TL;DR

A nano magnesium nourisher targets macrophages to reduce liver inflammation by inhibiting harmful immune responses and promoting tissue repair.

Contribution

A macrophage-targeted nanoscale Mg2⁺ nourisher is developed to specifically inhibit NLRP3 inflammasome-driven inflammation in liver disease.

Findings

Targeted Mg2⁺ delivery to macrophages inhibits NLRP3 inflammasome activation and pyroptosis.

MgC@PS treatment enhances Kupffer cell resilience and upregulates antioxidant genes.

Incorporating stem cell components improves intestinal barrier integrity and accelerates tissue repair.

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 Mg2⁺ (iMg2+) delivery by exploiting macrophages’ efferocytosis in response to phosphatidylserine. It is found that targeted enrichment of magnesium ions (Mg2⁺) 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 iMg2⁺ 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.

This report describes a nano magnesium nourisher, named MgC@PS, capable of targeted Mg2⁺ delivery to macrophages, effectively suppressing The nuclear factor kappa B (NF‐κB) activation and mitigating NLRP3 inflammasome‐driven pyroptosis in liver inflammation. Integrated with stem cell vesicle encapsulation, MgC@PS_SCV safeguards Kupffer cells, alleviates oxidative stress, reduces inflammatory monocyte infiltration, and accelerates tissue repair, presenting a promising approach for managing gut‐liver inflammatory disorders.

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