Pro-Inflammatory Vicious Cycle-Normalizing Biomimetic Nanoparticles to Treat Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS), characterized by inflammation-induced pulmonary reactive oxygen species (ROS) elevation, causes severe alveolar epithelial cells damage and promotes M1 polarization of alveolar macrophages (AMs). M1-polarized AMs generate substantial ROS and potent pro-inflammatory cytokines, triggering a widespread secondary inflammatory cascade. Therefore, ARDS is trapped in a vicious "ROS-M1 macrophages polarization-inflammation-ROS" cycle, which markedly exacerbates disease progression. Constrained by this, previous monotargeted therapeutic approaches exhibited suboptimal efficacy and failed to meet clinical needs. Herein, a vicious cycle-normalizing strategy was introduced to target the dual pathogenic mediators in the ARDS microenvironment. Specifically, phosphatidylserine-modified and metformin-loaded biomimetic honeycomb manganese dioxide nanoparticles (PS-HM/M NPs) were developed, with superoxide dismutase (SOD) and catalase (CAT)-mimetic properties to eliminate excessive intracellular ROS while metformin efficiently promotes phenotypic transition of AMs toward the pro-resolution M2 state. In an acute lung injury (ALI) model, PS-HM/M NPs successfully interrupted the malignant cycle and significantly resolved inflammation. In conclusion, this work highlighted the critical role of regulating the ROS-macrophage crosstalk and provided a promising avenue for ARDS therapy.