Abstract

Background Sepsis-induced acute lung injury (ALI) is a severe complication characterized by uncontrolled inflammation and high mortality, yet effective targeted therapies remain limited. Notably, acute myocardial infarction (MI) frequently coexists with or exacerbates ALI through shared inflammatory pathways. Dexamethasone (Dex) exerts potent anti-inflammatory effects but its clinical application is limited by non-specific biodistribution and dose-dependent off-target toxicities. Methods We developed a biomimetic nanoplatform Dex@mPLGA by coating dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles with RAW264.7 macrophage membranes. The physicochemical properties of Dex@mPLGA were systematically characterized. Cellular uptake, cytotoxicity, anti-inflammatory, antioxidant, anti-apoptotic, and immunomodulatory effects were evaluated in LPS-stimulated RAW264.7 cells. In vivo biodistribution, therapeutic efficacy, and biosafety were further evaluated in an LPS-induced ALI mouse model. Results Dex@mPLGA exhibited a core–shell structure with an average particle size of 147.3 nm, negative surface charge, 3.2% drug loading, 74.6% encapsulation efficiency, good colloidal stability, and sustained Dex release. SDS-PAGE analysis supported the retention of macrophage membrane protein components in the final formulation. Dex@mPLGA was internalized by RAW264.7 macrophages in a time-dependent manner and showed minimal cytotoxicity at the tested concentrations. In LPS-stimulated macrophages, Dex@mPLGA alleviated inflammatory and oxidative stress-related responses relative to the LPS model, including improved cell viability, reduced ROS and MDA levels, decreased pro-inflammatory cytokine and NO production, increased IL-10 secretion, reduced apoptosis, restored proliferative activity, and modulation of macrophage polarization. Direct comparison with uncoated Dex@PLGA showed that the additional in vitro benefit of macrophage membrane coating was endpoint-de