Abstract Rationale Severe asthma remains a challenging respiratory condition with limited biomarkers and therapeutic targets. Matrix metalloproteinase 12 (MMP12) has been implicated in pathogenesis of inflammatory diseases associated with macrophages. However, its role in severe asthma and the underlying mechanisms are not fully understood. Methods we confirmed the role of MMP12 in severe asthma using a Mmp12-/- mice, and designed an albumin-based nanoparticle to actively deliver the Aderamastat (Aderamastat-BSA NPs) to lung tissue. Specifically, we evaluated the enrichment of Aderamastat-BSA NPs and its retention time in lung tissue, and then compared the efficiency of Aderamastat and Aderamastat-BSA on the expression of MMP12 in vitro and in vivo, and on the airway inflammation and mucus expression in severe asthma mice model. Results In this study, we found MMP12 was significantly upregulated in severe asthma patients and positively correlated with eosinophilic inflammation. In severe asthma mice, MMP12, primarily expressed by monocyte-derived alveolar macrophages, was found to exacerbate airway inflammation and mucus hypersecretion by promoting pulmonary vascular hyperpermeability. Mechanistically, IL-4 and LPS act synergistically to promote MMP12 expression in macrophages via the STAT6 pathway. Furthermore, an inhaled albumin nanoparticle-based formulation of a specific MMP12 inhibitor, Aderamastat, effectively targeted alveolar macrophages, demonstrated sustained lung retention, and significantly ameliorated disease pathology at a lower dose than systemic administration. Conclusion Our study identifies MMP12 as a key driver of severe asthma pathogenesis and presents a promising targeted nanotherapeutic strategy for its treatment. This abstract is funded by: no
Xu et al. (Fri,) studied this question.