ROS-responsive nanogels enable inhaled CD24 immunotherapy for selective hyperinflammation suppression in severe pneumonia.

Acute pneumonia triggered by pathogen infection and lung injury persists as a critical global life-threatening issue. Cluster of differentiation 24 (CD24), by selectively inhibiting the inflammatory response associated with damage-associated molecular patterns (DAMPs) through the interaction with Siglec, has appeared as a unique paradigm to alleviate acute pneumonia, yet its effective pulmonary delivery remains challenging. Here, we report on reactive oxygen species (ROS)-responsive and mucus-penetrable nanogels (ROSμNG) for pulmonary CD24 delivery to rescue acute pneumonia by selective inhibition of hyperinflammatory response. CD24-loaded nanogels (CD24-ROSμNG) exhibit excellent stability during nebulization, efficient mucus penetration, and inflammation-triggered CD24 release, affording over 80% drug enrichment in lung tissues through nebulization inhalation. In lipopolysaccharide-induced severe acute pneumonia mouse models, nebulized CD24-ROSμNG effectively attenuates cytokine storm, suppresses DAMP-mediated inflammation, and mitigates lung injury, achieving an over 3.5-fold increase in survival rate compared to intravenous administration of over 12-fold higher dose of free CD24. In an H1N1 virus influenza model, CD24-ROSμNG not only prevents cytokine storm but also preserves neutrophil-mediated viral clearance by limiting excessive neutrophil extracellular trap formation, thereby avoiding uncontrolled inflammation while maintaining antiviral defenses. These inhalable CD24 nanogels establish a strategy to manage pulmonary hyperinflammatory disorders.