Triptolide-loaded MSC membrane nanoparticles with enhanced pulmonary accumulation for the treatment of acute lung injury: from network pharmacology to experimental validation

Abstract

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are critical conditions with few effective therapies. Triptolide (TPL), a bioactive compound from Tripterygium wilfordii, exhibits potent anti-inflammatory effects but its clinical use is restricted by poor solubility, rapid clearance, and hepatotoxicity. Using network pharmacology and molecular docking as hypothesis-generating approaches, we prioritized NLRP3 inflammasome activation as a key candidate pathway mediating the therapeutic effects of TPL against ALI. Based on this, we developed mesenchymal stem cell membrane-coated TPL-loaded biomimetic nanoparticles (CM@TPL-NPs) comprising a PLGA core loaded with TPL and coated with mesenchymal stem cell membranes. This coating improved biocompatibility, reduced hepatic sequestration, and enabled preferential lung accumulation, while retaining inherent anti-inflammatory activity. CM@TPL-NPs showed favorable physicochemical properties, sustained release, and improved biocompatibility. Mechanistically, they suppressed NLRP3 inflammasome activation in LPS-stimulated macrophages, while preserving endothelial barrier integrity. In a murine ALI model, both intravenous and intranasal CM@TPL-NPs administration reduced inflammation, cytokine levels, oxidative stress, and histopathological damage. Intranasal (IN) instillation demonstrated enhanced pulmonary accumulation and therapeutic efficacy, positioning it as a promising non-invasive strategy. Importantly, the nanoformulation significantly reduced hepatotoxicity compared with free TPL. Overall, CM@TPL-NPs provide a potent, lung-accumulating platform for ALI therapy via modulation of the NLRP3 inflammasome, supporting further preclinical investigation.