Nebulized Polygonum cuspidatum-derived nanovesicles loaded with dexamethasone synergistically ameliorate acute lung...

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.

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.

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.

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.