{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:03:47Z","timestamp":1790093027852,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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-\u03baB 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1872209","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:26:17Z","timestamp":1790090777000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Nebulized Polygonum cuspidatum-derived nanovesicles loaded with dexamethasone synergistically ameliorate acute lung injury via metabolic-immune reprogramming"],"prefix":"10.3389","volume":"17","author":[{"given":"Zibin","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Lab of Respiratory Disease, Guangzhou Medical University","place":["Guangzhou, China"]},{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University","place":["Shenzhen, 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