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

ABSTRACT

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.