Theranostics · 2026
Targeted RNA Therapy Reprograms Fibrotic Macrophages to Reverse Pulmonary Fibrosis.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Song Zhimin, Chen Jingjing, Fan Jiaying, Zhang Tinghong, Peng Xing, Pan Yao, Zhang Yun, Wang Yaofeng, Qin Jinling, Meng Shu
Аннотация
RATIONALE: Pulmonary fibrosis is driven by maladaptive immune programs that reinforce fibroblast activation. We sought to determine whether profibrotic macrophage states could be therapeutically remodeled to alleviate fibrosis through targeted RNA-based modulation of their intrinsic regulatory circuitry.
METHODS: Integrated single-cell transcriptomic and metabolomic analyses were performed to identify regulatory programs associated with profibrotic macrophage states during lung fibrosis. A mannose-functionalized lipid nanoparticle platform was developed to preferentially deliver regulatory RNAs to CD206⁺ macrophages in vivo. Therapeutic efficacy was evaluated by Arg1 silencing or targeted delivery of Irf5 mRNA to assess macrophage state remodeling in fibrotic lungs.
RESULTS: Transcriptomic and metabolomic analyses identified an Arg1-centered metabolic module that stabilizes profibrotic macrophage states during lung fibrosis. The mannose-functionalized lipid nanoparticle system enabled preferential RNA delivery to CD206⁺ macrophages in vivo. Arg1 silencing disrupted profibrotic metabolic programs, whereas targeted delivery of Irf5 mRNA transcriptionally redirected macrophages toward an inflammatory, antifibrotic state, resulting in attenuation of pulmonary fibrosis.
CONCLUSIONS: These findings demonstrate that macrophage states can be therapeutically remodeled through targeted RNA-based modulation in pulmonary fibrosis. This strategy establishes state-level immune reprogramming as a potentially generalizable approach for dismantling pathogenic immune programs in fibrotic disease.
METHODS: Integrated single-cell transcriptomic and metabolomic analyses were performed to identify regulatory programs associated with profibrotic macrophage states during lung fibrosis. A mannose-functionalized lipid nanoparticle platform was developed to preferentially deliver regulatory RNAs to CD206⁺ macrophages in vivo. Therapeutic efficacy was evaluated by Arg1 silencing or targeted delivery of Irf5 mRNA to assess macrophage state remodeling in fibrotic lungs.
RESULTS: Transcriptomic and metabolomic analyses identified an Arg1-centered metabolic module that stabilizes profibrotic macrophage states during lung fibrosis. The mannose-functionalized lipid nanoparticle system enabled preferential RNA delivery to CD206⁺ macrophages in vivo. Arg1 silencing disrupted profibrotic metabolic programs, whereas targeted delivery of Irf5 mRNA transcriptionally redirected macrophages toward an inflammatory, antifibrotic state, resulting in attenuation of pulmonary fibrosis.
CONCLUSIONS: These findings demonstrate that macrophage states can be therapeutically remodeled through targeted RNA-based modulation in pulmonary fibrosis. This strategy establishes state-level immune reprogramming as a potentially generalizable approach for dismantling pathogenic immune programs in fibrotic disease.