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 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 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.