Abstract
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.