Hydrogen-induced disruption of the airway mucus barrier enhances nebulized RNA delivery to reverse pulmonary fibrosis

作者：Chang Liu, Xidong Tian, Zhenping Wang, Jcw Mak, Shirui Mao, Tzu‐Ming Liu, Ying Zheng · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adt2752 · 被引用次数：13 · 研究领域：Hydrogen's biological and therapeutic effects、Inhalation and Respiratory Drug Delivery、Respiratory Support and Mechanisms

Nebulized RNA therapies are well suited for treating respiratory diseases, in particular pulmonary fibrosis (PF); however, effective delivery remains challenging. In this study, we present a highly efficient aerosol inhalation system that enables high levels of in vivo transfection efficiency in lung macrophages, yielding durable responses against PF. First, we established a nose-only aerosol inhalation device integrated with a hydrogen supplement system. This setup enables the precise administration of lipid nanoparticles (LNPs) at a controlled low dose, while simultaneously delivering the optimal concentration of therapeutic hydrogen gas. We further developed a hybrid lipid NP (HNP) by hybridizing a pH-dependent charge-inverting lipid film with apoptotic T cell membranes to enhance endosomal escape and trigger macrophage production of hepatocyte growth factor for lung repair. We demonstrated that the hydrogen flow–induced shear stresses disrupt the NP-mucus interaction, enhancing the deposition of aerosolized HNPs/ TGF β 1 siRNA within fibrotic lung lesions, effectively blocking fibrogenic signaling pathways and offering a clinically viable strategy for combating PF.