褪黑素调节的mRNA负载脂质纳米粒增强NRF2介导的间充质干细胞治疗肺纤维化
Melatonin-tuned mRNA-loaded lipid nanoparticles enhance NRF2-mediated mesenchymal stem cell therapy for pulmonary fibrosis.
摘要(中文译文)
肺纤维化的特征在于持续性氧化应激和细胞外基质过度沉积，然而有效的治疗策略仍然有限。在此，我们报道了一种纳米工程策略，将褪黑素和Nrf2 mRNA整合于脂质纳米颗粒（LNPs）中，对间充质干细胞（MSCs）进行功能性工程化改造，以实现氧化还原靶向的抗纤维化治疗。分子动力学模拟和膜流动性分析揭示，褪黑素可调节富含胆固醇的LNP膜中的脂质堆积，增加膜流动性并促进内体逃逸，从而改善mRNA的胞质递送。这种膜水平的调控实现了高效的Nrf2表达，并促进了工程化MSCs的抗氧化表型。这些治疗性LNP（TN）工程化的MSCs在上皮损伤模型和博来霉素诱导的肺纤维化小鼠模型中表现出增强的细胞保护性和抗纤维化活性。其治疗效应与上皮-间充质转化和细胞外基质重塑的抑制相关。总体而言，本研究确立了褪黑素驱动的膜调控作为一种有效策略，可增强LNP介导的mRNA递送，并实现MSCs的功能性工程化改造，用于氧化还原靶向的再生治疗。
Abstract
Pulmonary fibrosis is characterized by persistent oxidative stress and excessive extracellular matrix deposition, yet effective therapeutic strategies remain limited. Here, we report a nanoengineering strategy that integrates melatonin and Nrf2 mRNA within lipid nanoparticle (LNPs) to functionally engineer mesenchymal stem cells (MSCs) for redox-targeted antifibrotic therapy. Molecular dynamics simulations and membrane fluidity analyses revealed that melatonin modulates lipid packing in cholesterol-rich LNP membranes, increasing membrane fluidity and facilitating endosomal escape, thereby improving cytosolic mRNA delivery. This membrane-level tuning enabled efficient Nrf2 expression and promoted an antioxidant phenotype in the engineered MSCs. These therapeutic LNP (TN)-engineered MSCs exhibited enhanced cytoprotective and antifibrotic activities in epithelial injury models and in a bleomycin-induced pulmonary fibrosis mouse model. The therapeutic effects were associated with suppression of epithelial-mesenchymal transition and extracellular matrix remodeling. Collectively, this study establishes melatonin-driven membrane modulation as an effective strategy to enhance LNP-mediated mRNA delivery and enable functional engineering of MSCs for redox-targeted regenerative therapy.
如何引用
AMA
Ji Sun Park, Bobeen Cho, Seong Gi Lim, Yeeun Lee, Hayoung Jeon, In-Beom Kim, et al. Melatonin-tuned mRNA-loaded lipid nanoparticles enhance NRF2-mediated mesenchymal stem cell therapy for pulmonary fibrosis.. Biomaterials. 2027; doi:10.1016/j.biomaterials.2026.124531.
APA
Ji Sun Park, Bobeen Cho, Seong Gi Lim, Yeeun Lee, Hayoung Jeon, In-Beom Kim, et al (2027). Melatonin-tuned mRNA-loaded lipid nanoparticles enhance NRF2-mediated mesenchymal stem cell therapy for pulmonary fibrosis.. Biomaterials. https://doi.org/10.1016/j.biomaterials.2026.124531
GB/T 7714
Ji Sun Park, Bobeen Cho, Seong Gi Lim, Yeeun Lee, Hayoung Jeon, In-Beom Kim, et al. Melatonin-tuned mRNA-loaded lipid nanoparticles enhance NRF2-mediated mesenchymal stem cell therapy for pulmonary fibrosis.[J]. Biomaterials, 2027 doi:10.1016/j.biomaterials.2026.124531.
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