Targeted RNA Therapy Reprograms Fibrotic Macrophages to Reverse Pulmonary Fibrosis.

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.