Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options and high mortality rate. Pyroptosis mediated by gasdermin D (GSDMD) has been linked to disease advancement by releasing pro-fibrotic mediators, whereas the serum amyloid P component (SAP) shows anti-fibrotic properties. In this study, we designed a pulmonary mucus-penetrating lipid nanoparticle delivery system, known as DAS-lipid nanoparticle (DAS-LNP), to enable the simultaneous administration of GSDMD-targeting small interfering RNA (siRNA) and SAP-expressing plasmid DNA (si/pD-DAS-LNP). The formulation showed enhanced mucus penetration (approximately 2.2-fold) and improved endo-lysosomal escape, leading to a 3.5-fold increase in lung accumulation of the nucleic acid drug compared to the free drug group, and a 1.5-fold increase relative to the standard MC-LNP (MC-LNP) group at 24 h post-administration. Both in vitro and in vivo studies indicated a favorable safety profile for DAS-LNP. In a bleomycin-induced IPF mouse model, si/pD-DAS-LNP alleviated pulmonary inflammation, reduced pro-fibrotic factor levels, inhibited extracellular matrix deposition, improved lung function, and enhanced survival rates. The delivery efficiency enabled reduced dosage and administration frequency without compromising efficacy, thereby enhancing treatment compliance. These results suggest that concurrent inhibition of GSDMD and enhancement of SAP offer a complementary approach to modulate pyroptosis and the fibrotic microenvironment in IPF. The structure of DPPC/AS-modified LNP facilitates the effective pulmonary co-delivery of siRNA and pDNA, positioning si/pD-DAS-LNP as a promising translational strategy for IPF treatment. 3
