Nebulized Polygonum cuspidatum-derived nanovesicles loaded with dexamethasone synergistically ameliorate acute lung injury via metabolic-immune reprogramming.

Background: Systemic glucocorticoid therapy for acute lung injury (ALI) is frequently limited by poor pulmonary targeting and severe systemic side effects. To address these challenges, we developed a bio-inspired, inhalable nanoplatform using naturally derived nanovesicles from the medicinal plant Polygonum cuspidatum (PcDNs) to actively deliver dexamethasone (PcDNs@Dex) via nebulization. Methods: We assessed the post-nebulization stability of the nanosystem and evaluated its therapeutic efficacy in vitro and in vivo. In vitro, we investigated macrophage polarization (M1/M2) and the associated signaling pathways. Untargeted metabolomics was employed to analyze metabolic reprogramming. In vivo, a murine lipopolysaccharide (LPS)-induced ALI model was utilized to assess pulmonary targeting, alveolar damage, vascular permeability, and cytokine production. Results: Unlike conventional inert synthetic carriers, PcDNs function as intrinsic synergistic therapeutics. PcDNs@Dex maintained robust structural and functional stability post-nebulization, ensuring efficient targeted pulmonary delivery. In vitro, PcDNs@Dex exerted superior anti-inflammatory and cytoprotective effects by actively reprogramming macrophages from a pro-inflammatory M1 to a pro-resolving M2 phenotype, synergistically mediated through the coordinated inhibition of NF-κB and JAK-STAT signaling pathways. Crucially, untargeted metabolomics unveiled a novel immunometabolic mechanism: PcDNs inherently act as bioactive modulators that restore glycerophospholipid metabolic homeostasis, thereby stabilizing cell membranes and restricting pro-inflammatory mediator production at the metabolic level. In an LPS-induced ALI model, nebulized PcDNs@Dex precisely targeted the pulmonary niche, significantly attenuating alveolar damage, reducing vascular permeability, and suppressing the local cytokine storm. Conclusion: This dual intervention effectively promoted a reparative immune microenvironment while exhibiting excellent systemic safety. These results establish PcDNs@Dex as a promising, multi-target strategy that integrates targeted delivery with synergistic bioactivity for managing inflammatory lung diseases.