The inflammatory process plays a crucial role in the onset/progression of several lung pathologies including cystic fibrosis (CF), and the involvement of nuclear factor-κB (NF-κB ) is widely recognized. The specific inhibition of NF-κB by decoy oligonucleotides delivered in the lung may be beneficial although rationally designed systems are needed to optimize their pharmacological response. Prompted by this, here we have developed and tested in vivo an inhalable dry powder for prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPP) based on poly(lactic-co-glycolic) acid (PLGA). First, LPP containing dec-ODN (dec-ODN LPP) have been engineered to meet aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release and to preserve its structural integrity in lung lining fluids. Then, we have investigated the effects of dec-ODN LPP in a rat model of lung inflammation induced by intra-tracheal aerosolization of lipopolysaccharide (LPS) from P. aeruginosa. The results show that a single intra-tracheal insufflation of dec-ODN LPP reduced bronchoalveolar neutrophil infiltration induced by LPS up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate was associated to a reduced NF-κB/DNA binding activity as well as interleukin-6 (IL-6), interleukin-8 (IL-8) and mucin-2 (MUC2) mRNA expression in lung homogenates. It is worthy of note that the developed LPP, preventing the accumulation of neutrophils and NF-κB-related gene expression, may provide a new therapeutic option for local treatment of inflammation associated with lung diseases.