Engineered Exosomes Delivering Curcumin Show Promise Against Phosgene-Induced Lung Injury

Phosgene, a choking agent once deployed in chemical warfare and still a serious hazard in industrial accidents, has long lacked a targeted therapy. Once inhaled, it destroys the alveolar epithelial barrier, triggers runaway inflammation and floods the lungs with edema fluid, leaving clinicians with little more than supportive care in the form of mechanical ventilation and fluid management. A new study published in Bioengineering & Translational Medicine reports a nanotherapeutic platform that may change that picture: exosomes engineered to carry a transcription factor called myeloid ecotropic viral integration site 1, or Meis1, and loaded with the natural anti-inflammatory compound curcumin. In both cell culture and mouse models of phosgene-induced acute lung injury, the dual-cargo particles, dubbed Meis1-Exo@Cur, reduced inflammation, oxidative stress and cell death while measurably restoring lung function.

The research began with a search for molecular drivers of the injury. The team exposed mice to phosgene gas at a concentration of 8.33 milligrams per cubic meter for ten minutes, then profiled gene expression in lung tissue using high-throughput RNA sequencing. The analysis revealed 111 differentially expressed genes, with enrichment in apoptosis and in the PI3K-Akt, MAPK, HIF-1 and NF-κB signaling pathways. To narrow the field, the researchers applied machine learning: a least absolute shrinkage and selection operator regression filtered the gene list, and a random forest classifier ranked the remaining candidates. Four feature genes emerged—Meis1, Hif1a, Hif3a and Relb—and Meis1 stood out as the only one significantly downregulated in injured lungs. Western blotting confirmed the same suppression at the protein level. According to the authors, neither the expression pattern nor the functional role of Meis1 in phosgene-induced lung injury had been reported before.

Meis1 belongs to the three amino acid loop extension family of transcription factors and is best known for its roles in hematopoietic stem cell maintenance, cardiovascular development and metabolic regulation. To test whether it also protects the lung, the researchers created a stable line of MLE-15 mouse alveolar epithelial cells overexpressing the gene via lentiviral transduction. When these cells were injured with phosgene and lipopolysaccharide, overexpression of Meis1 significantly improved viability, cut apoptosis rates, lowered levels of the pro-apoptotic proteins cleaved caspase-3 and Bax, raised the anti-apoptotic protein Bcl2, and reduced both intracellular reactive oxygen species and lactate dehydrogenase release, a marker of membrane damage. The results positioned Meis1 as a plausible protective regulator of the alveolar epithelium and set the stage for a delivery strategy built around it.

That strategy exploits mesenchymal stem cell-derived exosomes, nanoscale vesicles that cells use to exchange bioactive molecules. Exosomes are attractive drug carriers because they are biocompatible, weakly immunogenic and naturally home to injured tissue, aided by surface molecules such as CXCR4 and integrins that favor accumulation at inflammatory sites, including the lung. The team engineered mesenchymal stem cells to overexpress Meis1, then isolated the resulting exosomes by ultracentrifugation and ultrafiltration. Transmission electron microscopy showed the typical round vesicular morphology, and nanoparticle tracking analysis placed both ordinary and engineered vesicles in the 30 to 150 nanometer range. Western blots confirmed the canonical exosomal markers CD9, CD63, CD81 and TSG101, while the negative marker Calnexin was absent. A protease K protection assay indicated that the added Meis1 protein sits on or tightly associates with the exosomal membrane, mirroring the digestion pattern of the membrane protein CD63 rather than the luminal cargo TSG101.

Curcumin, the polyphenol from turmeric, has well-documented anti-inflammatory, antioxidant and anti-apoptotic activity, but its clinical use has been hampered by poor water solubility, chemical instability and low bioavailability. Encapsulating it inside the engineered exosomes addressed those weaknesses. Using an optimized incubation method, the researchers achieved a drug loading content of 8.5 percent and a loading efficiency of 75.2 percent, verified by ultraviolet-visible spectrophotometry. Fluorescence labeling showed that MLE-15 cells efficiently internalized both Meis1-Exo and Meis1-Exo@Cur within 24 hours. Dose-response testing in injured cells identified 50 micrograms per milliliter as the effective concentration, where the benefit of treatment plateaued, and head-to-head comparisons showed that plain exosomes produced only weak, statistically insignificant effects, whereas Meis1-Exo and especially Meis1-Exo@Cur significantly rescued cell viability and suppressed apoptosis, oxidative stress and the release of the inflammatory cytokines TNF-α, IL-6 and IL-1β.

Mechanistically, the platform appears to work by simultaneously braking pro-inflammatory signaling and accelerating antioxidant defense. Western blotting showed that Meis1-Exo@Cur reduced the phosphorylation of proteins in the NF-κB and MAPK pathways, two central hubs of the inflammatory response, while increasing expression of the transcription factor Nrf2 and its downstream target heme oxygenase-1, the backbone of cellular antioxidant protection. The authors argue that this coordinated, multi-pathway modulation is precisely what single-target drugs have lacked in acute lung injury, where inflammation, oxidative damage and cell death reinforce one another in a rapidly progressing cascade.

In vivo results reinforced the cellular findings. Mice with phosgene-induced lung injury received tail vein injections of the various exosome formulations. Plain exosomes produced only marginal changes, but Meis1-Exo significantly improved tidal volume, minute ventilation and respiratory rate, lowered dynamic lung resistance and raised compliance as measured by the FlexiVent system, and restored residual volume and total lung capacity toward normal. Meis1-Exo@Cur outperformed both. Histology showed reduced inflammatory infiltration, the lung wet-to-dry weight ratio confirmed less edema, TUNEL staining revealed fewer dying cells, and enzyme-linked immunosorbent assays documented sharp drops in inflammatory cytokines in bronchoalveolar lavage fluid and lung tissue. Biosafety checks found no body weight loss, no histological damage to the heart, liver, spleen, lungs or kidneys, and normal serum levels of creatine kinase, lactate dehydrogenase, transaminases, creatinine and urea.

Biodistribution imaging helped explain the strong efficacy. After intravenous injection of fluorescently labeled particles, signal accumulated strongly in the lungs within one hour, peaked at four hours and remained elevated for up to twelve, a retention window the authors describe as therapeutically critical. At four hours, mean fluorescence intensity in lung tissue significantly exceeded that of the heart, liver, spleen and kidneys, and high-performance liquid chromatography confirmed that curcumin itself concentrated in the lungs in the same pattern. The study also probed the immune microenvironment. RNA sequencing of treated lungs identified 2,275 differentially expressed genes, with key pro-inflammatory cytokines downregulated and Meis1 restored. CIBERSORT analysis and in vivo flow cytometry converged on a consistent shift: neutrophils and pro-inflammatory M1 macrophages fell to near-baseline levels, while reparative M2 macrophages and immunosuppressive regulatory T cells rose, a phenotypic swing from inflammatory to reparative programs that the authors link directly to tissue healing.

Proteomic analysis added a second molecular layer. Of 3,231 proteins identified, 54 were significantly differentially expressed, and 27 molecules overlapped between the transcriptomic and proteomic datasets, with pathway enrichment again pointing to MAPK, NF-κB and TNF signaling as well as necroptosis and apoptosis. The authors also describe a subtle but meaningful effect on the mode of cell death: treatment shifted cells away from late apoptotic and necrotic states toward early apoptosis, a transition considered favorable because apoptotic cells are quietly cleared by macrophages rather than bursting and provoking secondary inflammation. The study has limits the authors acknowledge candidly. All animal work used male C57BL/6 mice, leaving sex-specific responses unexamined; the findings rest on a single phosgene model; the functional roles of individual immune subsets remain to be dissected; and long-term safety, exosome stability and large-scale preclinical validation are still ahead. Even so, the work marks the first report of Meis1’s involvement in acute pulmonary injury and demonstrates, with imaging and quantitative drug data, that engineered mesenchymal stem cell exosomes can co-deliver a regulatory protein and a hydrophobic small molecule to the injured lung. If those results translate, the platform could offer a template not only for treating phosgene exposure but for exosome-based precision therapy across inflammatory lung diseases, from acute respiratory distress syndrome to pulmonary fibrosis.

Subject of Research: An engineered exosome platform delivering Meis1 and curcumin for treating phosgene-induced acute lung injury

Article Title: Innovative myeloid ecotropic viral integration site 1‐engineered exosome platform combating oxidative stress and inflammation in acute pulmonary damage

Article References: Zhang, Y., Pang, K., Ling, Z., Wang, S., Hu, B., Deng, S., & Yang, Z. (2026). Innovative myeloid ecotropic viral integration site 1‐engineered exosome platform combating oxidative stress and inflammation in acute pulmonary damage. Bioengineering & Translational Medicine, 11(5), Article e70150. https://doi.org/10.1002/btm2.70150

Image Credits: AI Generated

DOI: 10.1002/btm2.70150

Keywords: acute lung injury, phosgene, exosomes, Meis1, curcumin, mesenchymal stem cells, NF-κB, Nrf2/HO-1, oxidative stress, inflammation, nanomedicine, immune microenvironment