Mannose-Modified Tobacco Mosaic Virus-Mediated Macrophage Regulation Inhibits Pulmonary Fibrosis Progression

Idiopathic pulmonary fibrosis (IPF) is a chronic disease, causing irreversible lung scarring and respiratory failure. CD206⁺ M2 macrophages play a key role in its progression. In this study, we utilize the pro-inflammatory properties of plant viruses to develop a mannose-modified tobacco mosaic virus nanoparticle (TMV-OEG8-Man), which targets and reprograms profibrotic macrophages to inhibit IPF. TMV-OEG8-Man alters the CD206⁺ M2 macrophage phenotype in vitro, suppressing profibrotic genes (Mrc1, Spp1, Ccr2) and signaling pathways (MAPK, TGF-beta, PI3K-Akt, mTOR, Wnt), thereby reducing the transition of fibroblasts to myofibroblasts. When administered via aerosol, TMV-OEG8-Man achieves prolonged lung retention with minimal systemic exposure. In mice with bleomycin-induced pulmonary fibrosis, a single dose during fibroproliferation attenuated fibrosis progression, increasing survival rate from 50% to 100%, and preserving lung architecture. This study establishes plant viral nanoparticles as a macrophage reprogramming strategy with therapeutic potential for organ fibrosis.