A potassium-based single-atom catalyst enables acute lung injury immunotherapy in mice by inhibiting macrophage pyroptosis.

Acute lung injury (ALI), which can have a mortality rate approaching 40%, lacks effective therapies. Macrophage pyroptosis represents a pro-inflammatory event and a potential therapeutic target. Here, we report a single-atom immunomodulator, a potassium-based single-atom catalyst (K-SAC) with K-N4 sites, that suppresses macrophage pyroptosis for ALI therapy through antioxidant catalysis. Constructed from biocompatible potassium, the most abundant intracellular metal in humans, K-SAC displays potent superoxide dismutase- and catalase-like activities, with the underlying mechanisms revealed by density functional theory simulations. Following preferential macrophage uptake, K-SAC scavenges reactive oxygen species, downregulates gasdermin D and its N-terminal fragment, activates endosomal sorting complexes required for transport-mediated membrane repair, and promotes membrane phospholipid remodeling, thereby effectively inhibiting macrophage pyroptosis. Notably, this catalytic membrane repair mechanism offers a versatile strategy for restoring membrane integrity. Such catalytic inhibition of pyroptosis preserves pulmonary immune homeostasis and ameliorates lipopolysaccharide- or cecal ligation and puncture-induced ALI, establishing a catalytic immunotherapeutic approach using a physiologically abundant element for therapeutic applications.