ROS-responsive nanogels enable inhaled CD24 immunotherapy for selective hyperinflammation suppression in severe pneumonia
Wang Xin1, Zhao Xiaofe1, Zhang Fan4, Wang Siyu1,2,3, Meng Fenghua1,2,3, Deng Chao(邓超)1,2,3*, Ye Mingzhou(叶明舟)4*, Zhong Zhiyuan(钟志远)1,2,3,5*
1Biomedical Polymers Laboratory, Soochow University, Suzhou 215123, China.
2Jiangsu Key Laboratory of Advanced Functional Polymer Materials, College of Chemistry, Chemical Engineering, and Materials Science, Suzhou 215123, China
3State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
4Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China
5College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Sci. Adv. 2026,12,eaec3712
Abstract: 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.
Article information: https://doi.org/10.1126/sciadv.aec3712