Background <p>Our previous work showed that exposure to multi-walled carbon nanotubes (MWCNTs) exacerbates allergic lung disease in mice induced by house dust mite extract (HDME). Furthermore, mice genetically deficient in the proteinase-activated receptor 2 (PAR2) exhibited reduced airway fibrosis after co-exposure to MWCNTs and HDME. The objective of this study was to determine whether inhibition of PAR2 signaling, using the monoclonal antibody SAM-11, attenuates MWCNT exacerbation of HDME-induced allergic lung disease.</p> Methods <p>C57BL/6J mice were exposed to MWCNTs in the presence or absence of HDME via oropharyngeal aspiration over a 21-day protocol. SAM-11 or isotype control antibodies were administered prior to exposure. Bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed for markers of allergic inflammation, airway remodeling, and fibrosis.</p> Results <p>SAM-11 treatment significantly reduced airway collagen deposition, eosinophilic inflammation, mucous cell metaplasia, and CD3⁺ T cell lung infiltration induced by co-exposure to MWCNTs and HDME. SAM-11 treatment also reduced lung mRNA expression of mediators involved in allergic lung disease (<i>Col1a</i>,<i> Tgf-b1</i>, <i>Arg-1</i>,<i> Il-33</i>,<i> Muc5b</i>), as well as STAT6 and Arg-1 protein in lung tissue.</p> Conclusion <p>Inhibition of canonical PAR2 signaling using SAM-11 attenuates multiple features of MWCNT-enhanced allergic lung disease with broader efficacy than PAR2-deficient models. These findings highlight PAR2 as a viable therapeutic target in allergic lung disease and asthma, suggesting that antibody-based blockade is a promising strategy for mitigating allergen and particle-induced disease.</p>