Biomimetic dexamethasone-loaded nanoparticles attenuate sepsis-induced acute lung injury

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.

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.

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-dependent rather than universal. Statistically significant coating-associated improvements were mainly observed in cell viability, IL-10 secretion, EdU-positive proliferative recovery, and M2 polarization, whereas several inflammatory, oxidative stress-related, apoptotic, and M1-polarization readouts were comparable between Dex@PLGA and Dex@mPLGA. In vivo, Dex@mPLGA showed improved pulmonary accumulation in inflamed lung tissues, improved survival outcomes, reduced systemic pro-inflammatory cytokine levels, and alleviated lung histopathological injury. Short-term biosafety evaluation showed no obvious organ toxicity or abnormal serum biochemical changes under the tested conditions.

Dex@mPLGA represents an innovative biomimetic Dex delivery platform with therapeutic potential for sepsis-induced ALI. Its efficacy is likely associated with PLGA-mediated sustained Dex delivery, macrophage-associated uptake, selected membrane-related immunoregulatory benefits, and improved pulmonary accumulation in vivo. However, the incremental in vitro advantage of Dex@mPLGA over Dex@PLGA was modest and endpoint-dependent, and the membrane coating should be interpreted as providing selected auxiliary benefits rather than uniformly enhancing all biological outcomes. Further studies are needed to validate membrane-specific targeting and long-term safety in more physiologically relevant models.