Structure-guided design of nucleosome-inspired nanoparticles for overcoming pulmonary barriers in fibrotic lung gene therapy

Treating pulmonary fibrosis (PF), a progressive and fatal lung disease, remains a great challenge. Here, we report a nucleosome-inspired peptide MNM designed to overcome mucus and cellular barriers, which achieved pulmonary si<i>TGF-</i>β<i>1</i> delivery efficiently for PF therapy. By mimicking histone-mediated DNA packaging, we engineered MNM with three functional modules: a histone-mimetic small interfering RNA (siRNA) binder, a membrane-penetrating domain, and a hydrophilic mucus-diffusing sequence. MNM integrates mucus penetration, cellular uptake, and endosomal escape into one platform, achieving highly efficient pulmonary siRNA delivery. MNM-si<i>TGF-</i>β<i>1</i> nanoparticles suppressed profibrotic gene expression and inflammation, which notably improved survival and reduced collagen deposition in aggressive PF models. This work establishes a biomimetic strategy to overcome complex biological barriers, advancing siRNA therapy for PF. Beyond si<i>TGF-</i>β<i>1</i> delivery for PF therapy, MNM's modular design is adaptable to messenger RNA, circular RNA, and other nucleic acids, offering a transformative platform for precision nanomedicine in pulmonary and systemic diseases.