The treatment and management of COPD by inhalation to the lungs has emerged as an attractive alternative route to oral dosing due to higher concentrations of the drug being administered to site of action. In this study, Nanocomposite Microparticles (NCMPs) of microRNA (miR-146a) containing PGA-co-PDL nanoparticles (NPs) for dry powder inhalation were formulated using l-leucine and mannitol. The spray-drying (Buchi B290) process was optimised and used to incorporate NPs into NCMPs using mix of l-leucine and mannitol excipients in different ratios (F1; 100:0% w/w, F2; 75:25% w/w, F3; 50:50% w/w, F4; 25:75% w/w, F5; 0:100% w/w) to investigate yield %, moisture content, aerosolisation performance and miR-146a biological activity. The optimum condition was performed at feed rate 0.5 ml/min, aspirator rate 28 m/h, atomizing air flow rate 480 L/h, and inlet drying temperature 70 °C which produced highest yield percentage and closest recovered NPs size to original prior spray-drying. The optimum formulation (F4) had a high yield (86.0 ± 15.01%), recovered NPs size after spray-drying 409.7 ± 10.05 nm (initial NPs size 244.8 ± 4.40 nm) and low moisture content (2.02 ± 0.03%). The aerosolisation performance showed high Fine Particle Fraction (FPF) 51.33 ± 2.9%, Emitted Dose (ED) of 81.81 ± 3.0%, and the mass median aerodynamic diameter (MMAD) was ≤5 µm suggesting a deposition in the respirable region of the lungs. The biological activity of miR-146a was preserved after spray-drying process and miR-146a loaded NCMPs produced target genes IRAK1 and TRAF6 silencing. These results indicate the optimal process parameters for the preparation of NCMPs of miR-146a-containing PGA-co-PDL NPs suitable for inhalation in the treatment and management of COPD.