Abstract

Idiopathic pulmonary fibrosis progressive lung stiffening from collagen and poor repair, therapies only partially help. • Dual-action RNA mHGF/siIL-11@C-LNP antifibrotic plus epithelial repair “weeding and root removal”. • Inhalable platform targeting the fibrotic niche, a promising strategy for solid organ fibrosis. Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung stiffening from excessive collagen deposition and impaired alveolar repair, yet current therapies offer only partial, transient relief. Here, we present an inhalable dual-action RNA platform (mHGF/siIL-11@C-LNP) that employs a coordinated “weeding and root removal” strategy aimed at reprogramming established fibrotic foci and restoring disrupted alveolar epithelium, thereby reversing IPF. The C-LNP comprises a hepatocyte growth factor (HGF) mRNA and interleukin-11 (IL-11) small interfering RNA (siRNA)-based core, functionalized with fibroblast activation protein (FAP)-targeting peptide arms and a collagenase I shell. Upon inhalation, the mHGF/siIL-11@C-LNP exhibits an optimal aerodynamic profile, enabling efficient deep lung deposition and penetration into fibrotic foci through the direct degradation of the collagen-rich extracellular matrix. The precise targeted co-delivery of mHGF and siIL-11 to collagen-producing myofibroblasts achieves synergistic effects, resulting in successful remodeling of the fibrotic lung microenvironment, characterized by reduced pro-fibrotic immune cells infiltration, a 71.3% reduction in pathological collagen, and amplified regenerative signaling that promotes epithelial restoration. This versatile inhalable platform not only represents a dual RNA-loaded nanocarrier system for IPF therapy but also offers a promising strategy for solid organ fibrosis by addressing the universally recognized fibrotic niche. Download: Download high-res image (191KB) Download: Download full-size image