Inhalable ROS-Responsive Biguanide-Functionalized Chitosan Nanoparticles for Catalase Delivery and Pulmonary Immunomodulation in Acute Lung Injury

Acute lung injury (ALI) is characterized by excessive inflammation and oxidative stress, with limited effective pharmacological treatments. Herein, we developed a ROS-responsive nanoplatform, termed GCS−CAT@TK, consisting of a self-assembled core formed by biguanide-functionalized chitosan (GCS) and catalase (CAT), coated with a thioketal-linked PEGylated lipid (DSPE-TK-PEG2000) shell. GCS−CAT@TK sequentially facilitated mucus penetration, enhanced cellular internalization, and enabled ROS-responsive CAT release in inflamed lungs. In a lipopolysaccharide-induced ALI mouse model, GCS−CAT@TK effectively scavenged excess ROS, interrupted the self-amplifying cycle of oxidative stress, and promoted pulmonary tissue repair. Furthermore, GCS−CAT@TK effectively reduced neutrophil infiltration, shifted macrophages toward an anti-inflammatory phenotype, and increased regulatory T-cell abundance, thereby remodeling the pulmonary immune microenvironment. Mechanistic analyses indicated that these therapeutic effects were associated with modulation of NF-κB pathway and restoration of epithelial junction integrity. Collectively, GCS−CAT@TK offers a promising approach to ROS-responsive enzyme delivery and immune regulation for ALI therapy.