A safe and anti-inflammatory plant-derived nanovesicle platform for targeted delivery in acute lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with extremely high mortality rates, for which effective and safe therapeutic strategies remain limited. The development of targeted and biocompatible drug delivery systems is urgently needed to control pulmonary inflammatory cascades while minimizing systemic toxicity. Plant-derived extracellular vesicles offer a naturally safe and anti-inflammatory platform for therapeutic delivery. Ginsenoside Rb1 (GRb1), a major bioactive compound from ginseng, possesses potent anti-inflammatory and anti-apoptotic properties, whereas lemon-derived EVs (LEVs) exhibit intrinsic antioxidant and anti-inflammatory effects. Here, we engineered a multifunctional, biocompatible drug delivery platform, GRb1@LEVs-cRGD, in which ginsenoside Rb1 is incorporated into and fused with LEVs to form hybrid bio-nanovesicles, while the vesicle surface is functionalized with cyclic RGD (cRGD) peptides to target integrin αvβ3 highly expressed in inflamed pulmonary tissues, thereby enhancing site-specific delivery. In vitro and in vivo studies confirmed that GRb1@LEVs-cRGD effectively inhibited M1 macrophage polarization, suppressed inflammatory cascades, and preserved epithelial-endothelial integrity. Furthermore, exogenous cholesterol loading improved vesicle stability, maintained the pH gradient, and enhanced the loading efficiency of tigecycline and vancomycin by six-fold. In murine models of bacterial pneumonia induced by carbapenem-resistant Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus , antibiotic-loaded GRb1@LEVs-cRGD efficiently accumulated at infection sites and exhibited synergistic anti-inflammatory and bactericidal effects. Overall, this study demonstrates that GRb1@LEVs-cRGD is a safe, targeted, and multifunctional therapeutic platform with significant potential for ALI/ARDS treatment. • A safe and anti-inflammatory plant-derived nanovesicle platform was created via membrane fusion. • This platform possesses excellent targeting capability toward inflamed lung tissues, thereby significantly enhancing drug accumulation at specific sites and minimizing off-target effects. • This platform exhibits excellent biocompatibility and well-defined core therapeutic efficacy, directly targeting the key pathological mechanisms of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). • Through exogenous cholesterol loading, this platform achieves carrier optimization and upgrading, enhances vesicle stability, and improves the loading efficiency of antibiotics such as tigecycline and vancomycin by 6-fold. • This platform can achieve a synergistic anti-inflammatory and bactericidal effect in bacterial pneumonia models induced by multidrug-resistant bacteria.