Polyplex of peptide-mannan and RNA for intranasal delivery of TGF-β siRNA in treatment of pulmonary fibrosis

Pulmonary fibrosis is a progressive, severe respiratory disease, often considered terminal, with a typical life expectancy of only a few years. It is marked by excessive deposition of extracellular matrix proteins, driven by a complex interplay of profibrotic signaling pathways, including contributions from monocyte-derived alveolar macrophages (Mo-AMs) and various immune and stromal cells. In this study, we present a peptide-mannan conjugate nanoparticle (PMNP) platform for the targeted delivery of transforming growth factor-β small interfering RNA (TGF-β siRNA) aimed at halting and reversing pulmonary fibrosis. The nanoparticles of TGF-β siRNA and peptide-mannan conjugates, generated through a solvent-free and easily scalable process, were administered intranasally to specifically target the alveolar macrophage population. In fibrotic models, these nanoparticles effectively reduced Mo-AM infiltration, reprogrammed the macrophage phenotype, and significantly reduced collagen deposition. Our findings suggest that intranasal delivery of TGF-β siRNA via PMNP offers a promising, easily self-assembled, and patient-friendly therapeutic approach for the treatment of lung fibrosis. • Peptide–mannan conjugate targets fibrotic alveolar macrophages via airway delivery. • Solvent-free process yields stable RNA-loaded peptide–mannan nanoparticle (PMNP). • TGF-β siRNA reprograms pro-fibrotic macrophages and reduce fibrosis.