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

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.