Reprogramming Lung Redox Homeostasis by NIR Driven Ultra‐Small Pd Loaded Covalent Organic Framework Inhibits NF‐κB Pathway for Acute Lung Injury Immunotherapy

Abstract Acute lung injury (ALI) refers to damage to lung related cells, typically caused by an uncontrollable inflammatory response, and over‐generated reactive oxygen species (ROS). Increasing evidence suggests that reprogramming lung redox homeostasis holds significant potentials for the clinical treatment of ALI. Herein, the simple synthesis of ultra‐small Pd loaded covalent organic framework (COF) (TP@Pd) is reported, which, when combined with near infrared (NIR) irradiation, exhibits nanozyme functionalities, including multiple enzyme mimicking activities and broad spectrum ROS scavenging, thereby promoting tissue repair for ALI immunotherapy. Mechanistically, through the therapeutic strategy of TP@Pd+NIR, the damaged cells and tissues are ameliorated by decreasing intracellular ROS levels (total ROS, ·OH and ·O 2 − ), downregulating inflammatory cytokines levels (IL‐6, TNF‐α and IL‐1β), upregulating antioxidant factor level (SOD2), inducing macrophage M2 directional polarization (downregulation of iNOS and CD86, and upregulation of IL‐10 and CD206), activating immunoregulation (CD4 + /CD8 + ratio increase), promoting tissue repair factor levels (upregulation of HSP70 and CD31), and suppressing the NF‐κB signaling pathway (downregulation of phosphorylated p65 and IκBα). Furthermore, following intravenous (IV) injection in rats, TP@Pd accumulated in lung tissue for 6 h, indicating the promising therapeutic efficacy via this administration route. Notably, the TP@Pd+NIR strategy demonstrated the excellent synergistic effects in alleviating lung inflammation storms, reducing diffuse alveolar damage, and accelerating lung tissue repair. Summarily, this work has designed a novel TP@Pd+NIR strategy for the synergistic enhancement of ALI amelioration, which may serve as a promising therapeutic approach for other ROS related diseases.