Neutrophil‐Membrane Camouflaged Nanoparticles for Dual Suppression of Pro‐Inflammatory Macrophages and Oxidative Stress in Septic Acute Lung Injury

ABSTRACT Management of sepsis‐associated acute lung injury (S‐ALI) remains challenging due to complex inflammatory cascades, oxidative stress amplification, and limited therapeutic delivery to injured pulmonary tissues. Here, we developed a biomimetic “dual‐lock‐inspired” nanoplatform (M@ORNP) that integrates a neutrophil‐mimetic membrane interface with an OR‐based encapsulated prodrug core to enable inflammation‐associated pulmonary targeting and coordinated therapeutic regulation. The platform consists of a self‐assembled ester‐linked prodrug composed of 4‐octyl‐itaconate and retinol, encapsulated within a membrane derived from differentiated HL‐60 cells. The neutrophil‐mimetic membrane endows M@ORNPs with enhanced interaction with inflammatory endothelial cells and promotes preferential accumulation within injured lung tissues. Following cellular internalization, M@ORNPs exhibited progressive dissociation from lysosomal compartments, consistent with altered endo‐lysosomal trafficking behavior and potential intracellular release of therapeutic components. In vitro and in vivo studies demonstrated that M@ORNPs coordinated the suppression of reactive oxygen species (ROS) accumulation and inflammatory signaling pathways, including NF‐κB, STAT1, and the NLRP3 inflammasome, in macrophage‐associated inflammatory models. In murine S‐ALI models, M@ORNP treatment reduced inflammatory responses, alleviated pulmonary injury, and improved survival outcomes under lethal challenge conditions. Collectively, this study presents a biomimetic nanotherapeutic strategy that combines inflammatory‐site accumulation with complementary anti‐inflammatory and antioxidant activities, providing a platform for the treatment of severe inflammatory disorders.