Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure. Environmental ImplicationParticulate matter (PM) is the major component of air pollution and causes a range of respiratory diseases. Airway inflammation is widely considered as the primary biological mechanism responsible for the respiratory health damage caused by PM exposure. Our study unveiled a novel regulatory mechanisms of PM-induced airway inflammation. We found that m6A-mediated HDAC9 upregulation promoted PM-induced airway inflammation by epigenetically controlling the DUSP9-MAPK axis and suppressing MEF2A. Furthermore, we developed a novel inhalable nanoparticle system for deliverying HDAC9 siRNA to treat PM-induced airway inflammation. Our study contributed to reducing the public health burden of respiratory diseases attributed to PM exposure.